A plasmin inhibitor, its preparation method and application

Abstract

The present invention relates to a plasmin inhibitor, a preparation method thereof and an application in the pharmaceutical field. Specifically, the present invention provides a compound represented by formula I, a preparation method thereof and an application in the pharmaceutical field, which relates to the field of medicinal chemistry. In formula I, R1 is H or halogen; R2 and R3 are each independently selected from H, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalicyclic group, substituted or unsubstituted heteroaryl; n = 0, 1 or 2. The compound provided by the present invention has high blood coagulation and hemostasis activities, high blood drug concentration and exposure in vivo, good safety, and has good clinical application prospects.

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly to a plasmin inhibitor, a preparation method thereof, and an application in the pharmaceutical field. Background Art

[0002] Plasmin is a proteolytic enzyme that can degrade fibrin. When tissue is damaged and blood vessels rupture, a hemostatic mechanism is triggered: blood vessels constrict, platelet plugs form, the coagulation process starts, and finally stable fibrin is formed. At the same time, due to the deposition of fibrin, the fibrinolytic system is activated, which maintains a balance between the formation and cleavage of fibrin and plays a role in maintaining blood vessel patency and remodeling damaged tissues during the repair of damaged blood vessel walls (Tengborn L, M, Berntorp E. Thromb Res. 2015 Feb; 135(2): 231-42).

[0003] The fibrinolytic system includes plasminogen, tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA). Plasminogen binds to lysine residues on the surface of fibrin and is converted into plasmin by activators (i.e., tPA) released from endothelial cells. Fibrinolysis inhibition can be used to treat bleeding. The use of antifibrinolytics can reduce blood loss in cardiac surgery, trauma, orthopedic surgery, solid organ transplantation, obstetrics and gynecology, neurosurgery, and non-surgical diseases (Ng W, Jerath A, M. Anaesthesiol Intensive Ther. 2015; 47(4): 339-50). In the early 1950s, it was found that lysine amino acids inhibited the activation of plasminogen, but the effect was too weak to be used to treat fibrinolytic bleeding diseases. In 1953, Shosuke Okamoto et al. showed that several sulfhydryl and amino carbonic acids had an effect on plasma proteins and found that the synthetic derivative of lysine, ε-aminocaproic acid (EACA), had a strong inhibitory effect on plasminogen. EACA has been widely used clinically, but in addition to minor gastrointestinal side effects such as nausea, large doses are also required. In 1962, 4-amino-methyl-cyclohexane-carboxylic acid (AMCHA) was discovered. This compound contains two stereoisomers, and further studies showed that its trans form (trans-4-aminomethylcyclohexanecarboxylic acid, i.e., tranexamic acid, TXA) had fibrinolytic inhibitory ability, with an activity about 10 times that of EACA and was proven to have stronger tolerance (Tengborn L, M, Berntorp E. Thromb Res. 2015 Feb; 135(2): 231-42).

[0004] Tranexamic acid is a synthetic lysine derivative and antifibrinolytic agent that can form a reversible complex with plasminogen. By binding to plasminogen, it blocks the interaction between plasminogen and the heavy chain of plasmin with fibrin lysine residues, thereby preventing the binding of plasminogen to the surface of fibrin and delaying fibrinolysis. Tranexamic acid has been approved for the treatment of severe menstrual bleeding and various surgical hemorrhagic diseases and is currently the most commonly used hemostatic drug in clinical practice. However, a large number of literature reports show that tranexamic acid is prone to cause gastrointestinal adverse reactions such as nausea, vomiting, diarrhea, and dyspepsia after oral administration, and its dosage is relatively large, and complications such as epilepsy may occur after patients take the drug.

[0005] Other hemostatic drugs of the same type, such as aminocaproic acid, have problems such as rapid excretion in the human body, weak hemostatic effect, short duration of action, and more toxic reactions. When the dosage is too large, thrombosis can form, which limits its application in those with a tendency to form thrombosis or a history of thrombotic vascular diseases and those with renal insufficiency. The mechanism of aminomethylbenzoic acid is the same as that of aminocaproic acid, and its effect is 4-5 times stronger than that of aminocaproic acid. It has a more significant effect on general chronic oozing bleeding, but has no hemostatic effect on traumatic bleeding and cancer bleeding. In addition, excessive dosage can also promote thrombosis. The hemostatic drug aprotinin commonly used in coronary artery bypass grafting was also withdrawn from the market by the FDA in 2008 due to its ability to induce renal failure, myocardial infarction, heart failure, etc.

[0006] Other hemostatic drugs with different mechanisms, such as carbazochrome acting on blood vessels, can induce epilepsy after repeated use; thrombin, a hemostatic drug that promotes the coagulation process, can only be applied to gastrointestinal bleeding or local bleeding.

[0007] In view of the fact that the hemostatic drugs available clinically are very limited and have certain defects more or less in terms of dosage, clinical indications, etc., and existing drugs of the same type all have problems such as large dosage, many adverse reactions, and prone to complications such as epilepsy, it is necessary to develop a new hemostatic drug to better meet the clinical needs. Summary of the Invention

[0008] On the one hand, the present invention provides a compound represented by Formula I, its pharmaceutically acceptable salts, hydrates, isomers, prodrugs, and mixtures thereof:

[0009]

[0010] Wherein, R1 is H or halogen;

[0011] R2 and R3 are each independently selected from H, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalicyclic group, substituted or unsubstituted heteroaryl group;

[0012] n = 0, 1 or 2.

[0013] In certain specific embodiments, each of R2 and R3 of the present invention is independently selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C6-C 10 aryl, substituted or unsubstituted C3-C6 cycloalkyl, substituted or unsubstituted C4-C 10 lipoheterocyclic group, substituted or unsubstituted C5-C 10 arylheterocyclic group.

[0014] In certain specific embodiments, each of R2 and R3 of the present invention is independently selected from substituted or unsubstituted methyl, substituted or unsubstituted ethyl, substituted or unsubstituted propyl, substituted or unsubstituted isopropyl, substituted or unsubstituted n-butyl, substituted or unsubstituted sec-butyl, substituted or unsubstituted isobutyl, substituted or unsubstituted tert-butyl.

[0015] In certain specific embodiments, R2 and R3 of the present invention are each independently substituted by one or more groups selected from alkyl, cycloalkyl, aryl or substituted aryl, halogen, amino, and hydroxyl.

[0016] In certain specific embodiments, R2 and R3 of the present invention are substituted by one or more groups selected from C1-C3 alkyl, C3-C6 cycloalkyl, substituted or unsubstituted C6-C 10 aryl, halogen, amino, and hydroxyl.

[0017] In certain specific embodiments, R2 and R3 of the present invention are substituted by one or more groups selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, benzyl, fluorine, chlorine, bromine, iodine, amino, and hydroxyl.

[0018] In certain specific embodiments, R2 of the present invention is selected from H, substituted or unsubstituted alkyl.

[0019] In certain specific embodiments, R2 of the present invention is substituted or unsubstituted C1-C6 alkyl.

[0020] In certain specific embodiments, the substituted C1-C6 alkyl of the present invention is substituted by one or more groups selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, benzyl, fluorine, chlorine, bromine, iodine, amino, and hydroxyl.

[0021] In certain specific embodiments, R2 of the present invention is selected from benzyl, 2-methylpropyl, neopentyl, phenethyl, isopropyl, propyl, 3,3-dimethylbutyl, isopentyl, 4-methoxyphenethyl, cyclohexylmethyl, cyclohexylethyl, and phenylpropyl.

[0022] In certain specific embodiments, R3 in the present invention is selected from hydrogen, hydroxyl, C1-C6 alkyl, C4-C 10 aliphatic heterocyclic group, C5-C 10 aromatic heterocyclic group.

[0023] In certain specific embodiments, R3 in the present invention is hydrogen.

[0024] The present invention provides the following compounds, their pharmaceutically acceptable salts, hydrates, isomers, prodrugs and mixtures thereof:

[0025] (1) 5,6,7,8-Tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0026] (2) 3-Fluoro-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0027] (3) 8-Hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0028] (4) 7-Benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0029] (5) 8-Morpholino-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0030] (6) 7-(2-Methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0031] (7) 7-Neopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0032] (8) 7-Phenethyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0033] (9) 7-Isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0034] (10) 7-Propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0035] (11) 7-(3,3-Dimethylbutyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0036] (12) 7-Isoamyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0037] (13) 7-(4-Methoxyphenethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0038] (14) 7-(Cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0039] (15) 7-(Cyclohexylethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid;

[0040] (16) 7-(3-Phenylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid.

[0041] Another object of the present invention is to provide a pharmaceutical composition comprising at least one of the foregoing compounds, or a pharmaceutically acceptable salt, hydrate, isomer, prodrug, and mixture thereof, and at least one pharmaceutically acceptable excipient.

[0042] Another object of the present invention is to provide the use of the foregoing compound or a pharmaceutically acceptable salt, hydrate, isomer, prodrug, and mixture thereof, or a pharmaceutical composition for the preparation of a drug.

[0043] In certain specific embodiments, the drug has therapeutic activities of promoting blood coagulation and hemostasis, and can be used for abnormal bleeding caused by hyperfibrinolysis, surgical operations, and postoperative bleeding, etc.

[0044] Another object of the present invention is to provide a method for treating and / or alleviating bleeding diseases or disorders, especially a method for treating and / or alleviating bleeding diseases such as abnormal bleeding caused by hyperfibrinolysis, surgical operations, and postoperative bleeding, etc., which comprises administering to a patient in need one or more of the foregoing pharmaceutical compositions or a compound of formula I or a pharmaceutically acceptable salt, hydrate, isomer, prodrug, or mixture thereof.

[0045] The pharmaceutically acceptable salt described in the present invention is a salt formed by the compound of formula I of the present invention and a pharmaceutically non-toxic acid or base, such as hydrochloride.

[0046] Term Definitions

[0047] Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this text, it is intended to refer to its corresponding product or its active ingredient.

[0048] The term "pharmaceutically acceptable" as used herein means suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic reaction, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio.

[0049] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention, which are prepared from compounds having specific substituents discovered in the present invention and relatively non-toxic acids or bases. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. For example, a representative pharmaceutically acceptable salt in the present invention is hydrochloride.

[0050] "Halogen" as used in the present invention refers to fluorine, chlorine, bromine and iodine.

[0051] "Alkyl" as used in the present invention refers to saturated aliphatic hydrocarbon groups. For example, "C1-C6 alkyl" refers to saturated aliphatic hydrocarbon groups having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, etc.

[0052] "Alkoxy" refers to -O-alkyl; for example: C1-C6 alkoxy refers to straight-chain or branched-chain alkoxy containing 1-6 carbons, and C1-C3 alkyl refers to straight-chain or branched-chain alkoxy containing 1-3 carbons. Typical alkoxys include but are not limited to methoxy, ethoxy, n-propoxy, isopropoxy, etc.

[0053] "Cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituents. For example, "C3-C6 cycloalkyl" refers to cycloalkyl containing 3 to 6 carbon atoms. Typical C3-C6 cycloalkyls include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, etc.

[0054] "Heteroalicyclic group" refers to saturated monocyclic hydrocarbon substituents in which one or more ring atoms are replaced by heteroatoms selected from N, O, S, and the remaining ring atoms are carbon. For example: "3-8 membered heteroalicyclic" refers to saturated cyclic hydrocarbon substituents containing 3-8 ring atoms, in which one or more ring atoms are replaced by heteroatoms selected from N, O, S, and the remaining ring atoms are carbon. Specific examples include but are not limited to: oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, piperidinyl, piperazinyl, morpholinyl, etc.

[0055] "Arylheterocyclic group" refers to an aromatic cyclic substituent in which one or more ring atoms are replaced by heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. For example, "5-6 membered arylheterocyclic group" refers to an aromatic heterocyclic group containing 5 to 6 ring atoms, and specific examples include, but are not limited to, pyridyl, pyrimidinyl, imidazolyl, pyridazinyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl.

[0056] "Aryl" refers to an aromatic ring group. For example, "6-10 membered aryl" refers to an aromatic ring group containing 6 to 10 carbon ring atoms. Examples of the aryl moiety include phenyl, naphthyl, etc.

[0057] "Optionally" means that the subsequently described event or condition may but does not necessarily occur. Detailed implementation mode

[0058] The synthesis methods of the compounds and intermediates of the present invention are illustrated by examples below. The following examples are only examples of the present invention and should not be construed as limiting the scope of the present invention. Unless otherwise specified, the raw materials and reagents involved in the present invention can be obtained through commercial channels, and the specific sources do not affect the implementation of the technical solution of the present invention.

[0059] Preparation of tert-butyl 2-chloro-7-formyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0060]

[0061] (1) Preparation of 2,3-bis(methoxycarbonyl)pyridine 1-oxide

[0062] Weigh dimethyl pyridine-2,3-dicarboxylate (4.90 g) and dissolve it in acetonitrile (60 mL). Add urea peroxide (4.71 g) under ice bath, and slowly add trifluoroacetic anhydride (10.5 g). After the addition is complete, the system becomes a clear solution. Heat it to room temperature and react for 4 hours. Quench with an aqueous solution of sodium metabisulfite. Add dichloromethane and water, separate the layers, and extract the aqueous phase with a mixed solvent (DCM / MeOH). Dry the organic phase with anhydrous sodium sulfate, filter by suction, and concentrate the filtrate to dryness to obtain the title compound (5.15 g).

[0063]

[0064] MS(ESI) m / z (M+H) + = 212.1.

[0065] (2) Preparation of dimethyl 6-chloropyridine-2,3-dicarboxylate

[0066] Weigh 2,3-bis(methoxycarbonyl)pyridine 1-oxide (5.15 g), add phosphorus oxychloride (30 mL) under ice bath, and heat up to 105 °C for reaction for 4 hours. Concentrate under reduced pressure, dilute with ethyl acetate, dropwise add to crushed ice, add aqueous sodium carbonate solution to adjust pH = 10, extract with ethyl acetate, and wash the organic phase with aqueous sodium chloride solution. Concentrate the organic phase to dryness, purify the obtained crude product by column chromatography to obtain the title compound (3.52 g).

[0067]

[0068] MS(ESI) m / z(M+H) + = 230.1

[0069] (3) Preparation of (6-chloropyridine-2,3-diyl)dimethanol

[0070] Weigh dimethyl 6-chloropyridine-2,3-dicarboxylate (3.50 g) and dissolve it in tetrahydrofuran (72 mL) and methanol (1.5 mL). Add lithium borohydride (0.84 g) portionwise under ice bath, and heat up to room temperature for reaction for 3 hours. Pour the reaction system into aqueous sodium bicarbonate solution, add ethyl acetate, perform liquid-liquid extraction, dry the organic phase with anhydrous sodium sulfate, filter by suction, and concentrate the filtrate to dryness to obtain the title compound (2.63 g).

[0071]

[0072] MS(ESI) m / z(M+H) + = 174.1

[0073] (4) Preparation of 6-chloro-2,3-bis(chloromethyl)pyridine

[0074] Weigh (6-chloropyridine-2,3-diyl)dimethanol (2.63 g), add thionyl chloride (40 mL) under ice bath, react at room temperature for 6 h, concentrate under reduced pressure, dilute with ethyl acetate, dropwise add to crushed ice, add aqueous sodium carbonate solution to adjust pH = 10, extract with ethyl acetate, and wash the organic phase with aqueous sodium chloride solution. Concentrate the organic phase to dryness, purify the obtained crude product by column chromatography to obtain the title compound (2.1 g).

[0075]

[0076] MS(ESI) m / z(M+H)+ = 210.1

[0077] (5) Preparation of dimethyl 6-acetyl-2-chloro-5,8-dihydro-1,6-dimethylpyrido[1,2-a]pyrimidine-7,7(6H)-dicarboxylate

[0078] Weigh 6-chloro-2,3-bis(chloromethyl)pyridine (2.10 g) and dissolve it in N,N-dimethylformamide (15 mL). Under an ice bath, successively add dimethyl acetamidomalonate (2.17 g) and sodium hydride (0.40 g). React at room temperature for 1 hour. Under an ice bath, add sodium hydride (0.40 g), react overnight at room temperature, add ethyl acetate and water, separate and extract. Concentrate the organic phase to dryness. Purify the obtained crude product by column chromatography to obtain the title compound (1.74 g).

[0079]

[0080] MS(ESI) m / z(M+H) + = 327.1

[0081] (6) Preparation of 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine-7-carboxylic acid hydrochloride

[0082] Weigh dimethyl 6-acetyl-2-chloro-5,8-dihydro-1,6-dimethylpyridine-7,7(6H)-dicarboxylate (1.74 g), add 6 M hydrochloric acid (15 mL), react under closed conditions at 100 °C for 4 hours. TLC shows that the reaction is complete. Concentrate the system under reduced pressure to dryness to obtain the title compound (1.16 g).

[0083]

[0084] MS(ESI) m / z(M+H) + = 213.1

[0085] (7) Preparation of methyl 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine-7-carboxylate hydrochloride

[0086] Weigh 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine-7-carboxylic acid hydrochloride (1.16 g) and dissolve it in methanol (20 mL). Slowly add thionyl chloride (1.67 g) dropwise under an ice bath. Heat to 70 °C and reflux for 3 hours. TLC shows that the reaction is complete. Concentrate the system under reduced pressure to dryness to obtain the title compound (1.23 g).

[0087]

[0088] MS(ESI) m / z(M+H) + = 227.1

[0089] (8) Preparation of 6-(tert-butyl)-7-methyl-2-chloro-7,8-dihydro-1,6-naphthyridine-6,7(5H)-dicarboxylate

[0090] Methyl 2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine-7-carboxylate hydrochloride (1.23 g) was weighed and dissolved in dichloromethane (25 mL). Triethylamine (1.89 g) and di-tert-butyl dicarbonate (1.53 g) were added successively. The reaction was carried out at room temperature for 1 hour, and TLC showed that the reaction was complete. Dichloromethane and water were added, and liquid-liquid extraction was performed. The organic phase was concentrated to dryness. The obtained crude product was purified by column chromatography to obtain the title compound (1.19 g).

[0091]

[0092] MS(ESI)m / z(M+H) + = 327.1.

[0093] (9) Preparation of 6-(tert-butoxycarbonyl)-2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine-7-carboxylic acid

[0094] 6-(tert-Butyl) 7-methyl 2-chloro-7,8-dihydro-1,6-naphthyridine-6,7(5H)-dicarboxylate (0.4 g) was dissolved in tetrahydrofuran (3 mL) / methanol (3 mL) / water (3 mL) at room temperature. Lithium hydroxide hydrate (0.1 g) was added, and the mixture was stirred and reacted for 1 hour. Under an ice bath, the pH was adjusted to 4 - 5 with dilute hydrochloric acid (1 M). Ethyl acetate / water liquid-liquid extraction was performed, and the organic phase was extracted with ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the title compound (0.369 g).

[0095]

[0096] MS(ESI)m / z(M+H) + = 313.1.

[0097] (10) Preparation of tert-butyl 2-chloro-7-(methoxy(methyl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0098] 6-(tert-Butoxycarbonyl)-2-chloro-5,6,7,8-tetrahydro-1,6-naphthyridine-7-carboxylic acid (0.374 g) was dissolved in dichloromethane (20 mL) at room temperature. N,N-Diisopropylethylamine (1.25 mL), 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.494 g), and methoxymethylamine hydrochloride (0.235 g) were added successively and stirred overnight. Dichloromethane / water liquid-liquid extraction was performed, and the organic phase was extracted with dichloromethane and washed with saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography to obtain the title compound (0.379 g).

[0099]

[0100] MS(ESI) m / z (M+H) + = 356.1

[0101] (11) Preparation of tert-butyl 2-chloro-7-formyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0102] Dissolve tert-butyl 2-chloro-7-(methoxy(methyl)carbamoyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (0.378 g) in anhydrous tetrahydrofuran (20 mL), add it under a nitrogen atmosphere, cool the system to -72 °C, add diisobutylaluminum hydride solution (1 M, 3.21 mL). After addition, slowly warm the system to room temperature and stir for 3 hours. Place the reaction system in an ice bath, add water dropwise to quench for 10 minutes, add saturated potassium sodium tartrate solution (20 mL), stir for 20 minutes, extract with ethyl acetate, combine the organic phases, dry over anhydrous sodium sulfate, filter, remove the solvent under reduced pressure, and purify the obtained crude product by silica gel column chromatography to obtain the title compound (0.206 g).

[0103]

[0104] MS(ESI) m / z (M+H) + = 297.0

[0105] Example 1 Preparation of 5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0106]

[0107] (1) Preparation of tert-butyl 2-(benzylthio)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0108] Weigh 2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate tert-butyl ester (450 mg), benzyl mercaptan (0.2 mL), tris(dibenzylideneacetone)dipalladium (66 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (84 mg) and N,N-diisopropylethylamine (0.48 mL) into a reaction flask, add 1,4-dioxane (6 mL), displace with argon 3 times, react at 90 °C for 6 hours, quench with water, extract twice with ethyl acetate, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain the title compound (600 mg).

[0109]

[0110] MS(ESI) m / z (M+H) + = 357.1

[0111] (2) Preparation of tert-butyl 2-(chlorosulfonyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0112] Weigh 2-(benzylthio)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate tert-butyl ester (300 mg), dissolve it in acetonitrile (5 mL), and successively add water (0.12 mL), acetic acid (0.19 mL), and 1,3-dichloro-5,5-dimethylhydantoin (316 mg) under an ice bath. Stir for 1 hour under an ice bath. Add saturated sodium bicarbonate solution to adjust the pH to weakly alkaline, extract twice with ethyl acetate, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain the title compound (174 mg).

[0113]

[0114] MS(ESI) m / z(M+H) + = 333.0.

[0115] (3) Preparation of sodium 6-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0116] Dissolve 2-(chlorosulfonyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate tert-butyl ester (174 mg) in tetrahydrofuran (3 mL) and water (3 mL), add sodium hydroxide (63 mg), and stir at 80 °C for 3 hours. Concentrate under reduced pressure to obtain the title compound (214 mg).

[0117]

[0118] MS(ESI) m / z(M+H) + = 315.0.

[0119] (4) Preparation of 5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0120] Weigh sodium 6-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate (60 mg), dissolve it in 6M hydrochloric acid solution (4 mL), and stir at room temperature for 1 hour. Concentrate the system to dryness and purify by Pre-HPLC to obtain the title compound (8.98 mg).

[0121]

[0122] MS(ESI) m / z(M+H) + = 215.0.

[0123] 11H NMR (400 MHz, Deuterium Oxide) δ 7.76 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 4.41 (s, 2H), 3.58 (t, J = 6.5 Hz, 2H), 3.17 (t, J = 6.5 Hz, 2H).

[0124] Example 2 Preparation of 3-Fluoro-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic Acid Hydrochloride

[0125]

[0126] (1) Preparation of tert-Butyl 2-(Benzylthio)-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

[0127] Weigh 2-Chloro-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylic acid tert-butyl ester (100 mg), benzyl mercaptan (130 mg), tris(dibenzylideneacetone)dipalladium(0) (32 mg), 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene (41 mg) and N,N-Diisopropylethylamine (90 mg) into a reaction flask, add 1,4-dioxane (5 mL), displace with nitrogen, react at 90 °C for 6 hours, concentrate under reduced pressure to dryness, and purify by column chromatography to obtain the title compound (100 mg).

[0128]

[0129] MS(ESI) m / z (M + H) + = 375.1.

[0130] (2) Preparation of tert-Butyl 2-(Chlorosulfonyl)-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

[0131] Weigh tert-Butyl 2-(Benzylthio)-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate (100 mg), dissolve it in acetonitrile (5 mL), and successively add acetic acid (64 mg), water (40 mg) and 1,3-Dichloro-5,5-dimethylhydantoin (105 mg) under ice bath. Stir for 1 hour under ice bath. Add ice water and dichloromethane, separate by liquid extraction, and concentrate the organic phase to dryness to obtain the title compound (90 mg).

[0132]

[0133] MS(ESI) m / z (M + H) + = 351.1.

[0134] (3) Preparation of 3-fluoro-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0135] Weigh 2-(chlorosulfonyl)-3-fluoro-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylic acid tert-butyl ester (90 mg), dissolve in tetrahydrofuran (3 mL) and water (3 mL), add sodium hydroxide (32 mg), and stir at 80°C for 1 hour. Add ethyl acetate and water, extract and discard the organic phase. Concentrate the aqueous phase to dryness, dissolve in 6M hydrochloric acid solution (3 mL), and stir at room temperature for 1 hour. Concentrate the system to dryness, and purify by pre-HPLC to obtain the title compound (36.4 mg).

[0136]

[0137] MS (ESI) m / z (M+H) + =232.9.

[0138] 1 H NMR (400MHz, D2O) δ7.52 (d, J = 9.8Hz, 1H), 4.22 (s, 2H), 3.36 (t, J = 6.3Hz, 2H), 3.00 (t, J = 6.2Hz, 2H).

[0139] Example 3 Preparation of 8-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0140]

[0141] (1) Preparation of tert-butyl 8-acetoxy-2-(benzylthio)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0142] Weigh 8-acetoxy-2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (978 mg) and dissolve it in 1,4-dioxane (10 mL). Add tris[dibenzylideneacetone]dipalladium (549.6 mg), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (694 mg), triethylamine (1.2 g) and benzyl mercaptan (744 mg) in sequence. Heat to 115° C. under a nitrogen atmosphere, react for 24 hours, concentrate in vacuo, and purify the crude product by column chromatography to obtain the title compound (900 mg).

[0143]

[0144] MS (ESI) m / z (M+H) + =415.2.

[0145] (2) Preparation of tert-Butyl 8-Acetoxy-2-(chlorosulfonyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0146] Weigh 8-acetoxy-2-(benzylthio)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (415 mg) into a dry reaction flask, dissolve it with acetonitrile, then successively add 1,3-dichloro-5,5-dimethylhydantoin (210 mg), glacial acetic acid (128 mg), and purified water (77 mg), and react at room temperature for two hours. Add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness to obtain the title compound (200 mg).

[0147]

[0148] MS(ESI) m / z (M+H) + = 391.1.

[0149] (3) Preparation of Sodium 6-(tert-Butoxycarbonyl)-8-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0150] Weigh 8-acetoxy-2-(chlorosulfonyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (200 mg), dissolve it in tetrahydrofuran (10 mL) and water (10 mL), add sodium hydroxide (22 mg), after addition, heat to 80 °C and stir for 1 hour, and remove the solvent under reduced pressure. Purify by reverse preparative column chromatography to obtain the title compound (80 mg).

[0151]

[0152] MS(ESI) m / z (M+H) + = 353.1.

[0153] (4) Preparation of 8-Hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic Acid Hydrochloride

[0154] Weigh 6-(tert-butoxycarbonyl)-8-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid sodium salt (80 mg) and dissolve it in water (5 mL), add dilute hydrochloric acid (0.5 M, 5 mL). React at room temperature for 1 hour, concentrate the reaction solution to dryness, and purify by pre-HPLC to obtain the title compound (35 mg).

[0155]

[0156] MS(ESI) m / z (M+H) + = 231.0.

[0157] 11H NMR (400 MHz, D2O) δ 7.85 (q, J = 8.3 Hz, 2H), 4.99 (s, 1H), 4.47 (dd, J = 34.2, 16.6 Hz, 2H), 3.64 (ddd, J = 36.2, 13.5, 2.6 Hz, 2H).

[0158] Example 4 Preparation of 7-Benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic Acid Hydrochloride

[0159]

[0160] (1) Preparation of tert-Butyl 7-Benzyl-2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0161] Weigh 2-chloro-7-formyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (300 mg) and dissolve it in 1,4-dioxane (20 mL). Add 4-methylbenzenesulfonyl hydrazide (186 mg), react at 80 °C for 1 hour, then add phenylboronic acid (183 mg) and potassium carbonate (207 mg). After the addition, reflux at 110 °C for 12 hours. Filter, wash the filter cake three times with ethyl acetate (10 mL × 3), concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (230 mg).

[0162]

[0163] MS (ESI) m / z (M + H) + = 358.9.

[0164] (2) Preparation of tert-Butyl 7-Benzyl-2-(benzylthio)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0165] Weigh tert-butyl 7-benzyl-2-chloro-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (230 mg) and dissolve it in 1,4-dioxane (10 mL). Add tris(dibenzylideneacetone)dipalladium (117 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (148 mg), triethylamine (259 mg), and benzyl mercaptan (159 mg) in sequence. Heat to 90 °C under a nitrogen atmosphere and react for 24 hours. Concentrate under vacuum, and purify the crude product by column chromatography to obtain the title compound (200 mg).

[0166]

[0167] MS (ESI) m / z (M + H) + = 446.6.

[0168] (3) Preparation of tert-butyl 7-benzyl-2-(chlorosulfonyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0169] Weigh 7-benzyl-2-(benzylthio)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate tert-butyl ester (200 mg) into a dry reaction flask, dissolve it with acetonitrile, and then successively add 1,3-dichloro-5,5-dimethylhydantoin (180 mg), glacial acetic acid (110 mg), and pure water (66 mg). React at room temperature for two hours, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness to obtain the title compound (200 mg).

[0170]

[0171] MS(ESI) m / z(M+H) + = 422.9.

[0172] (4) Preparation of sodium 7-benzyl-6-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0173] Weigh the crude product of tert-butyl 7-benzyl-2-(chlorosulfonyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (200 mg), dissolve it in tetrahydrofuran (5 mL) and water (5 mL), add sodium hydroxide (22 mg), heat to 80 °C and stir for 1 hour, and remove the solvent under reduced pressure. Purify by reverse preparative column chromatography to obtain the title compound (20 mg).

[0174]

[0175] MS(ESI) m / z(M+H) + = 405.1.

[0176] (5) Preparation of 7-benzyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0177] Weigh sodium 7-benzyl-6-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate (20 mg) and dissolve it in water (5 mL), add dilute hydrochloric acid (0.5 M 5 mL). React at room temperature for 1 hour. Concentrate the reaction solution to dryness and purify by pre-HPLC to obtain the title compound (7.0 mg).

[0178]

[0179] MS(ESI) m / z(M+H) + = 305.1.

[0180] 11H NMR (400 MHz, D2O) δ 7.76 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.39–7.33 (m, 2H), 7.30 (dd, J = 6.7, 4.2 Hz, 3H), 4.42 (d, J = 3.1 Hz, 2H), 4.02–3.95 (m, 1H), 3.22–3.04 (m, 4H).

[0181] Example 5 Preparation of 8-Morpholino-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic Acid Hydrochloride

[0182]

[0183] (1) Preparation of tert-Butyl 2-(Benzylthio)-8-hydroxy-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate

[0184] 8-Acetoxy-2-(benzylthio)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (500 mg) was weighed and dissolved in methanol (10 mL). Potassium carbonate was added, and the reaction was carried out at room temperature for 2 hours. The mixture was filtered, and the filter cake was washed three times with methanol. The filtrate was concentrated by evaporation, and the crude product was purified by column chromatography to obtain the title compound (400 mg).

[0185]

[0186] MS (ESI) m / z (M + H) + = 373.2.

[0187] (2) Preparation of tert-Butyl 2-(Benzylthio)-8-((Methanesulfonyl)oxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0188] tert-Butyl 2-(benzylthio)-8-hydroxy-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate (400 mg) was weighed into a dry reaction flask, dissolved in dichloromethane, and triethylamine (216.5 mg) was added. Methanesulfonyl chloride was slowly added dropwise under an ice bath. After the addition was complete, the reaction was carried out at room temperature for 2 hours. Water was added, and the mixture was separated and extracted. The organic phase was concentrated to dryness and purified by column chromatography to obtain the title compound (470 mg).

[0189]

[0190] MS (ESI) m / z (M + H) + = 451.1.

[0191] (3) Preparation of tert-Butyl 2-(Benzylthio)-8-morpholino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0192] Weigh 2-(benzylthio)-8-((methylsulfonyl)oxy)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (470 mg), dissolve it in N,N-dimethylformamide (5 mL) and acetonitrile (5 mL), add potassium carbonate (173 mg). After addition, heat to 65 °C and stir for 16 hours. Add ethyl acetate and water, separate the layers, extract, dry the organic phase to obtain the crude product, and purify it by column chromatography to obtain the title compound (450 mg).

[0193]

[0194] MS(ESI) m / z (M+H) + = 442.2

[0195] (4) Preparation of tert-butyl 2-(chlorosulfonyl)-8-morpholino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0196] Weigh 2-(benzylthio)-8-morpholino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (450 mg) into a dry reaction flask, dissolve it in acetonitrile, and then successively add 1,3-dichloro-5,5-dimethylhydantoin (394 mg), glacial acetic acid (240 mg), and purified water (144 mg), and react at room temperature for two hours.

[0197] Add ethyl acetate and water, separate the layers, extract, concentrate the organic phase to dryness to obtain the title compound (300 mg).

[0198]

[0199] MS(ESI) m / z (M+H) + = 418.1

[0200] (5) Preparation of sodium 6-(tert-butoxycarbonyl)-8-morpholino-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0201] Weigh 2-(chlorosulfonyl)-8-morpholino-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (300 mg), dissolve it in tetrahydrofuran (5 mL) and water (5 mL), add sodium hydroxide (29 mg). After addition, heat to 80 °C and stir for 1 hour, and evaporate under reduced pressure. Purify by reverse preparative column chromatography to obtain the title compound (100 mg).

[0202]

[0203] MS(ESI) m / z (M - 23 + H) + = 400.1

[0204] (7) Preparation of 8-Morpholino-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic Acid Hydrochloride

[0205] 6-(tert-Butoxycarbonyl)-8-morpholino-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sodium sulfonate (100 mg) was weighed and dissolved in water (5 mL). Dilute hydrochloric acid (0.5 M, 5 mL) was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was concentrated to dryness, and the title compound (35 mg) was obtained by reverse-phase preparative purification.

[0206]

[0207] MS(ESI) m / z(M+H) + = 300.09.

[0208] 1 H NMR(400 MHz, D2O) δ 7.99 (d, J = 8.2 Hz, 1H), 7.94 (d, J = 8.2 Hz, 1H), 5.21 (dd, J = 10.6, 6.3 Hz, 1H), 4.56 (t, J = 9.8 Hz, 2H), 4.25 (dd, J = 12.8, 6.3 Hz, 1H), 3.98 (d, J = 23.4 Hz, 4H), 3.95–3.89 (m, 1H), 3.47 (s, 2H), 3.33 (s, 2H).

[0209] Example 6 Preparation of 7-(2-Methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic Acid Hydrochloride

[0210]

[0211] (1) Preparation of 2-Methyl-N-(3-methylbut-1-en-2-yl)propane-2-sulfinamide

[0212] Isovaleraldehyde (6.90 g) was weighed and dissolved in dichloromethane (100 mL). tert-Butanesulfinamide (10.70 g), anhydrous magnesium sulfate (48.2 g), and pyridinium 4-methylbenzenesulfonate (1.00 g) were added successively. The mixture was heated to 40 °C and reacted for 2 hours, then cooled to room temperature, filtered by suction, the filter cake was washed with dichloromethane, and the filtrate was concentrated to dryness. The title compound (9.77 g) was obtained by column chromatography purification.

[0213]

[0214] MS(ESI) m / z(M+H) + = 190.1.

[0215] (2) Preparation of N-(1-(3-bromo-6-methoxypyridin-2-yl)-4-methylpentan-2-yl)-2-methylpropane-2-sulfinamide

[0216] Weigh 3-bromo-6-methoxy-2-methylpyridine (5.05 g) into a dry reaction flask, inject anhydrous tetrahydrofuran (100 mL) under a nitrogen atmosphere, and cool down to -78 °C. Dropwise add a tetrahydrofuran solution of lithium diisopropylamide (12.5 mL, 2.0 M), and react at -78 °C for 40 minutes. Dropwise add tetrahydrofuran (20 mL) containing 2-methyl-N-(3-methylbut-1-enyl)propane-2-sulfinamide (5.00 g), react at -30 °C for 30 minutes, slowly warm up to room temperature, detect that the reaction is complete by LC-MS, add saturated ammonium chloride solution to quench, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness. Purify by column chromatography to obtain the title compound (7.27 g).

[0217]

[0218] MS(ESI) m / z(M+H) + = 391.1, 393.1.

[0219] (3) Preparation of ethyl 6-methoxy-2-(4-methyl-2-((2-methylpropane-2-sulfinyl)amino)pentyl)pyridine-3-carboxylate

[0220] Weigh N-(1-(3-bromo-6-methoxypyridin-2-yl)-4-methylpentan-2-yl)-2-methylpropane-2-sulfinamide (3.91 g), dissolve it in ethanol (100 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (1.16 g) and N,N-diisopropylethylamine (2.02 g), replace the air in the system with carbon monoxide and stir at 100 °C in a carbon monoxide atmosphere for 24 hours, and remove the solvent under reduced pressure. Purify by column chromatography to obtain the title compound (3.48 g).

[0221]

[0222] MS(ESI) m / z(M+H) + = 343.2.

[0223] (4) Preparation of 2-methoxy-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5(6H)-one

[0224] Weigh ethyl 6-methoxy-2-(4-methyl-2-((2-methylpropan-2-ylsulfinyl)amino)pentyl)pyridine-3-carboxylate (3.45 g) and dissolve it in acetonitrile (60 mL). Add cesium carbonate (5.87 g). Heat to 80 °C and stir overnight. Monitor the reaction by LC-MS until completion. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (2.44 g).

[0225]

[0226] MS(ESI) m / z(M+H) + = 235.1

[0227] (5) Preparation of 2-hydroxy-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one

[0228] Weigh 2-methoxy-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-(6H)-one (2.4 g), add acetic acid solution of hydrobromic acid (20 mL), heat to 80 °C and stir for 2 hours. Remove the solvent under reduced pressure, add ethyl acetate for pulping, filter, and dry to obtain the crude title compound (1.56 g).

[0229]

[0230] MS(ESI) m / z(M+H) + = 221.1

[0231] (6) Preparation of 2-chloro-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one

[0232] Weigh 2-hydroxy-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one (1.54 g), add phosphorus oxychloride (20 mL), heat to 100 °C and stir for 2 hours. Remove the solvent under reduced pressure, add ice water and ethyl acetate, extract by liquid separation, concentrate the organic phase to dryness, and purify by column chromatography to obtain the title compound (1.66 g).

[0233]

[0234] MS(ESI) m / z(M+H) + = 239.1

[0235] (7) Preparation of tert-butyl 2-chloro-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

[0236] Weigh 2-chloro-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one (1.66 g), dissolve it in dichloromethane (50 mL), and successively add triethylamine (4.58 g), 4-dimethylaminopyridine (0.17 g), and di-tert-butyl dicarbonate (2.87 g). Heat to 40 °C and react for 2 hours. Concentrate under reduced pressure to dryness, and purify by column chromatography to obtain the title compound (1.89 g).

[0237]

[0238] MS(ESI) m / z (M+H) + = 339.1

[0239] (8) Preparation of tert-butyl 2-chloro-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

[0240] Weigh tert-butyl 2-chloro-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate (1.86 g), dissolve it in tetrahydrofuran (25 mL), and dropwise add a solution of borane in dimethyl sulfide (22 mL, 2.0 M) under an ice bath. Under nitrogen protection, react at 50 °C for 4 hours, dropwise add methanol to quench under an ice bath, concentrate under reduced pressure to dryness, and purify by column chromatography to obtain the title compound (0.62 g).

[0241]

[0242] MS(ESI) m / z (M+H) + = 325.0

[0243] (9) Preparation of tert-butyl 2-(benzylthio)-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

[0244] Weigh tert-butyl 2-chloro-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate (227 mg), benzyl mercaptan (130 mg), tris(dibenzylideneacetone)dipalladium(0) (64 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (81 mg), and triethylamine (180 mg) into a reaction flask, add 1,4-dioxane (5 mL), displace with nitrogen, react at 115 °C for 24 hours, concentrate under reduced pressure to dryness, and purify by column chromatography to obtain the title compound (250 mg).

[0245]

[0246] MS(ESI) m / z (M+H) + = 353.1

[0247] (10) Preparation of tert-Butyl 2-(Chlorosulfonyl)-7-(2-Methylpropyl)-5,6,7,8-Tetrahydro-1,6-Naphthyridine-6-Carboxylate

[0248] Weigh 2-(Benzylthio)-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate tert-butyl ester (200 mg), dissolve it in acetonitrile (5 mL), and successively add acetic acid (113 mg), water (68 mg), and 1,3-dichloro-5,5-dimethylhydantoin (185 mg) under an ice bath. Stir for 1 hour under an ice bath, add ice water and dichloromethane, separate the layers by liquid-liquid extraction, and concentrate the organic phase to dryness to obtain the title compound (121 mg).

[0249]

[0250] MS(ESI) m / z(M+H) + = 389.1.

[0251] (11) Preparation of Sodium 6-((tert-Butoxy)Carbonyl)-7-(2-Methylpropyl)-5,6,7,8-Tetrahydro-1,6-Naphthyridine-2-Sulfonate

[0252] Weigh 2-(Chlorosulfonyl)-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate tert-butyl ester (116 mg), dissolve it in tetrahydrofuran (5 mL) and water (5 mL), add sodium hydroxide (36 mg), stir at 80 °C for 1 hour, add ethyl acetate and water, separate the layers by liquid-liquid extraction, and concentrate the aqueous phase to dryness to obtain the title compound (120 mg).

[0253]

[0254] MS(ESI) m / z(M+H) + = 371.1.

[0255] (12) Preparation of 7-(2-Methylpropyl)-5,6,7,8-Tetrahydro-1,6-Naphthyridine-2-Sulfonic Acid Hydrochloride

[0256] Weigh sodium 6-((tert-butoxy)carbonyl)-7-(2-methylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate (120 mg), dissolve it in 0.5 M hydrochloric acid solution (3 mL), stir at room temperature for 1 hour, concentrate the system to dryness, and separate by pre-HPLC to obtain the title compound (39.06 mg).

[0257]

[0258] MS(ESI) m / z(M+H) + = 271.1.

[0259] 1 1H NMR (400 MHz, D2O) δ 7.77 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 4.43 (s, 2H), 3.75 (dd, J = 10.8, 4.6 Hz, 1H), 3.30 (dd, J = 18.2, 4.6 Hz, 1H), 2.94 (dd, J = 18.2, 10.8 Hz, 1H), 1.80–1.69 (m, 1H), 1.61 (t, J = 7.2 Hz, 2H), 0.87 (dd, J = 11.4, 6.5 Hz, 6H).

[0260] Example 7 Preparation of 7-neopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0261]

[0262] (1) Preparation of N-(3,3-dimethylbutylidene)-2-methylpropane-2-sulfinamide

[0263] Weigh 3,3-dimethylbutyraldehyde (8.01 g) and dissolve it in dichloromethane (120 mL). Then successively add tert-butanesulfinamide (10.67 g), anhydrous magnesium sulfate (48.15 g), and pyridinium 4-methylbenzenesulfonate (1.01 g). Heat to 40 °C and react for 24 hours. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (12.0 g).

[0264]

[0265] MS (ESI) m / z (M + H) + = 204.1.

[0266] (2) Preparation of N-(1-(3-bromo-6-methoxypyridin-2-yl)-4,4-dimethylpentan-2-yl)-2-methylpropane-2-sulfinamide

[0267] Weigh 3-bromo-6-methoxy-2-methylpyridine (8.08 g) into a dry reaction flask, inject anhydrous tetrahydrofuran (45 mL) under a nitrogen atmosphere, and cool the temperature to -78 °C. Dropwise add a solution of lithium diisopropylamide in tetrahydrofuran (22 mL, 2.0 M), and react at -78 °C for 40 minutes. Dropwise add tetrahydrofuran (40 mL) containing N-(3,3-dimethylbutylidene)-2-methylpropane-2-sulfinamide (8.93 g), react at -78 °C for 30 minutes, and slowly warm to room temperature. Detect that the reaction is complete by LC-MS, add saturated ammonium chloride solution to quench, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness.

[0268] Purify by column chromatography to obtain the title compound (14.0 g).

[0269]

[0270] MS(ESI) m / z(M+H) + = 405.1, 407.1.

[0271] (3) Preparation of ethyl 2-(2-((tert-butylsulfinyl)amino)-4,4-dimethylpentyl)-6-methoxynicotinate

[0272] Weigh N-(1-(3-bromo-6-methoxypyridin-2-yl)-4,4-dimethylpentan-2-yl)-2-methylpropane-2-sulfinamide (14.0 g), dissolve it in ethanol (120 mL), add [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium dichloromethane complex (4.24 g) and N,N-diisopropylethylamine (8.94 g). After adding, replace the gas in the system with carbon monoxide and react at 100 °C for 6 hours under a carbon monoxide atmosphere. Remove the solvent under reduced pressure and purify by column chromatography to obtain the title compound (6.28 g).

[0273]

[0274] MS(ESI) m / z(M+H) + = 399.1.

[0275] (4) Preparation of 6-(tert-butylsulfinyl)-2-methoxy-7-neopentyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0276] Weigh ethyl 2-(2-((tert-butylsulfinyl)amino)-4,4-dimethylpentyl)-6-methoxynicotinate (5.1 g) and dissolve it in acetonitrile (100 mL), add cesium carbonate (20.88 g). Heat to 80 - 90 °C and react for 6 hours, cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (4.03 g).

[0277]

[0278] MS(ESI) m / z (M+H) + = 353.1

[0279] (5) Preparation of 2-hydroxy-7-neopentyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0280] Weigh 6-(tert-butylsulfinyl)-2-methoxy-7-neopentyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one (4.03 g), add acetic acid solution of hydrobromic acid (10 mL), heat up to 80 °C and stir for 2 hours, remove the solvent under reduced pressure, add ethyl acetate for pulping, filter, dry, and obtain the crude product of the title compound (3.60 g).

[0281]

[0282] MS(ESI) m / z (M+H) + = 235.1

[0283] (6) Preparation of 2-chloro-7-neopentyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0284] Weigh 2-hydroxy-7-neopentyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one (3.60 g), add phosphorus oxychloride (15 mL), heat up to 100 °C and stir for 2 hours, remove the solvent under reduced pressure, add ice water and ethyl acetate, perform liquid-liquid extraction, and concentrate the organic phase to dryness. Purify by column chromatography to obtain the title compound (2.30 g).

[0285]

[0286] MS(ESI) m / z (M+H) + = 253.1

[0287] (7) Preparation of tert-butyl 2-chloro-7-neopentyl-5-oxo-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate

[0288] Weigh 2-chloro-7-neopentyl-7,8-dihydro-1,6-naphthyridin-5(6H)-one (2.20 g), dissolve it in dichloromethane (50 mL), and successively add triethylamine (4.41 g), 4-dimethylaminopyridine (0.21 g), and di-tert-butyl dicarbonate (5.71 g). Heat up to 40 °C and stir overnight. Monitor the reaction by LC-MS until completion. Concentrate to dryness under reduced pressure and purify by column chromatography to obtain the title compound (2.80 g).

[0289]

[0290] MS(ESI) m / z (M+H) + = 353.1

[0291] (8) Preparation of tert-butyl 2-chloro-7-neopentyl-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate

[0292] Weigh tert-butyl 2-chloro-7-neopentyl-5-oxo-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate (2.80 g), dissolve it in tetrahydrofuran (25 mL), and dropwise add a solution of borane in dimethyl sulfide (25 mL, 2.0 M) under an ice bath. Stir at 60 °C for 4 hours under nitrogen protection, dropwise add methanol to quench under an ice bath, and concentrate to dryness under reduced pressure. Purify by column chromatography to obtain the title compound (1.20 g).

[0293]

[0294] MS(ESI) m / z (M+H) + = 339.1

[0295] (9) Preparation of tert-butyl 2-(benzylthio)-7-neopentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0296] Weigh tert-butyl 2-chloro-7-neopentyl-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate (70 mg), benzyl mercaptan (50 mg), tris(dibenzylideneacetone)dipalladium (18 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg) and triethylamine (40 mg) into a reaction flask, add 1,4-dioxane (5 mL), displace with nitrogen, react overnight at 100 °C, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the title compound (70 mg).

[0297]

[0298] MS(ESI) m / z (M+H) + = 427.1

[0299] (10) Preparation of tert-butyl 2-(chlorosulfonyl)-7-neopentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0300] Weigh 2-(benzylthio)-7-neopentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (70 mg), dissolve it in acetonitrile (4 mL), and successively add acetic acid (40 mg), water (24 mg), and 1,3-dichloro-5,5-dimethylhydantoin (65 mg) under an ice bath. Stir for 1 hour under an ice bath, add ice water and dichloromethane, perform liquid-liquid extraction, and concentrate the organic phase to dryness to obtain the title compound (66 mg).

[0301]

[0302] MS(ESI) m / z (M+H) + = 403.1

[0303] (11) Preparation of sodium 6-(tert-butoxycarbonyl)-7-neopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0304] Weigh 2-(chlorosulfonyl)-7-neopentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (66 mg), dissolve it in tetrahydrofuran (3 mL) and water (3 mL), add sodium hydroxide (30 mg), stir at 80 °C for 1 hour, add ethyl acetate and water, perform liquid-liquid extraction, discard the organic phase, and concentrate the aqueous phase to dryness to obtain the title compound (60 mg).

[0305]

[0306] MS(ESI) m / z (M+H) + = 385.1

[0307] (12) Preparation of 7-neopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0308] Weigh the crude product of sodium 6-(tert-butoxycarbonyl)-7-neopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate (60 mg), dissolve it in 6 M hydrochloric acid solution (3 mL), stir at room temperature for 1 hour, concentrate the system to dryness, and separate by pre-HPLC to obtain the title compound (19 mg).

[0309]

[0310] MS(ESI) m / z (M+H) + = 285.1

[0311] 11H NMR (400 MHz, Deuterium Oxide) δ 7.86–7.62 (m, 2H), 4.43 (d, J = 2.1 Hz, 2H), 3.83–3.70 (m, 1H), 3.39 (dd, J = 18.2, 4.9 Hz, 1H), 3.03 (dd, J = 18.2, 10.3 Hz, 1H), 1.75–1.58 (m, 2H), 0.92 (s, 9H).

[0312] Example 8 Preparation of 7-Phenethyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic Acid Hydrochloride

[0313]

[0314] (1) Preparation of 2-Methyl-N-(3-phenylpropylidene)propane-2-sulfinamide

[0315] Weigh 3-phenylpropanal (10.0 g) and dissolve it in dichloromethane (100 mL). Then successively add tert-butylsulfinamide (12 g), anhydrous magnesium sulfate (48.28 g), and pyridinium 4-methylbenzenesulfonate (1 g). Heat to 40 °C and react for 24 hours. Cool to room temperature, filter by suction. Wash the filter cake with dichloromethane. Concentrate the filtrate to dryness and purify by column chromatography to obtain the title compound (12 g).

[0316]

[0317] MS (ESI) m / z (M+H) + = 238.1.

[0318] (2) Preparation of N-[1-(3-Bromo-6-methoxypyridin-2-yl)-4-phenylbutan-2-yl]-2-methylpropane-2-sulfinamide

[0319] Weigh 3-bromo-6-methoxy-2-methylpyridine (5 g) into a dry reaction flask. Inject anhydrous tetrahydrofuran (100 mL) under a nitrogen atmosphere and cool to -78 °C. Dropwise add a tetrahydrofuran solution of lithium diisopropylamide (12.4 mL, 2.0 M) and react at -78 °C for 40 minutes. Dropwise add a solution of 2-methyl-N-(3-phenylpropylidene)propane-2-sulfinamide (6.45 g) in tetrahydrofuran (20 mL) and react at -78 °C for 30 minutes. Slowly warm to room temperature. Detect the completion of the reaction by LC-MS. Quench with saturated ammonium chloride solution, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness. Purify by column chromatography to obtain the title compound (6.5 g).

[0320]

[0321] MS (ESI) m / z (M+H)+ = 439.1。

[0322] (3) Preparation of Ethyl 6-methoxy-2-{2-[(2-methylpropan-2-ylsulfinyl)amino]-4-phenylbutyl}pyridine-3-carboxylate

[0323] Weigh N-[1-(3-bromo-6-methoxypyridin-2-yl)-4-phenylbutan-2-yl]-2-methylpropan-2-sulfinamide (10.0 g), dissolve it in ethanol (200 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (3.7 g) and N,N-diisopropylethylamine (7.5 mL). After adding, the system is purged with carbon monoxide and reacted under reflux conditions in a carbon monoxide atmosphere for 12 hours, and then concentrated under reduced pressure. Purification by column chromatography gives the title compound (5.4 g).

[0324]

[0325] MS(ESI) m / z (M+H) + = 432.2。

[0326] (4) Preparation of 2-Methoxy-6-(2-methylpropan-2-ylsulfinyl)-7-(2-phenylethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one

[0327] Weigh ethyl 6-methoxy-2-{2-[(2-methylpropan-2-ylsulfinyl)amino]-4-phenylbutyl}pyridine-3-carboxylate (5.4 g) and dissolve it in acetonitrile (100 mL), then add cesium carbonate (12.3 g). Heat to 90 °C and stir overnight. Monitor the reaction by LC-MS until completion. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (3 g).

[0328]

[0329] MS(ESI) m / z (M+H) + = 387.1。

[0330] (5) Preparation of 2-Hydroxy-7-(2-phenylethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one

[0331] Weigh 2-methoxy-6-(2-methylpropan-2-ylsulfinyl)-7-(2-phenylethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one (3 g) and dissolve it in an acetic acid solution of hydrobromic acid (50 mL). Stir at 80 °C for 2 hours, concentrate the system, slurry with ethyl acetate, filter by suction, and dry the filter cake to obtain the title compound (5 g).

[0332]

[0333] MS(ESI) m / z (M+H) + = 269.1

[0334] (6) Preparation of 2-chloro-7-(2-phenylethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one

[0335] Weigh 2-hydroxy-7-(2-phenylethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one (2.1 g), add phosphorus oxychloride (20 mL), heat to 100 °C and stir for 2 hours. Remove the solvent under reduced pressure, add ethyl acetate, adjust the pH to 9 - 10 with sodium carbonate solution, extract with ethyl acetate, concentrate the organic phase, and purify by silica gel column chromatography to obtain the title compound (2.13 g).

[0336]

[0337] MS(ESI) m / z (M+H) + = 287.1

[0338] (7) Preparation of tert-butyl 2-chloro-5-oxo-7-(2-phenylethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

[0339] Weigh 2-chloro-7-(2-phenylethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one (2.1 g) and dissolve it in dichloromethane (100 mL). Add di-tert-butyl dicarbonate (7.2 mL), triethylamine (11.6 mL), and 4-dimethylaminopyridine (0.26 g), heat to 40 °C and stir overnight. Add water to the system and extract 3 times with dichloromethane. Dry and concentrate the organic phase and purify by column chromatography to obtain the title compound (2.3 g).

[0340]

[0341] MS(ESI) m / z (M+H) + = 387.1

[0342] (8) Preparation of tert-butyl 2-chloro-7-(2-phenylethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

[0343] Weigh tert-butyl 2-chloro-5-oxo-7-(2-phenylethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate (2.3 g) and dissolve it in dry tetrahydrofuran (2.3 mL) solution. Replace the gas with nitrogen 3 times, dropwise add 2M borane dimethyl sulfide solution (30 mL). After adding, heat the reaction to 50 °C and react for 4 hours. Concentrate under reduced pressure to dryness and purify by column chromatography to obtain the title compound (1.2 g).

[0344]

[0345] MS(ESI) m / z (M+H) + = 373.1

[0346] (9) Preparation of tert-Butyl 2-(Benzylthio)-7-Phenethyl-7,8-Dihydro-1,6-Naphthyridine-6(5H)-Carboxylate

[0347] Weigh 2-Chloro-7-Phenethyl-7,8-Dihydro-1,6-Naphthyridine-6(5H)-Carboxylate tert-Butyl Ester (230 mg) and dissolve it in 1,4-Dioxane (10 mL). Then, add Tris(Dibenzylideneacetone)Dipalladium(0) (117 mg), 4,5-Bis(Diphenylphosphino)-9,9-Dimethylxanthene (148 mg), Triethylamine (259 mg), and Benzyl Mercaptan (159 mg) in sequence. Heat the mixture to 115 °C under a nitrogen atmosphere and react overnight. Concentrate the reaction mixture under vacuum and purify it by column chromatography to obtain the title compound (200 mg).

[0348]

[0349] MS(ESI) m / z (M+H) + = 461.2

[0350] (10) Preparation of tert-Butyl 2-(Chlorosulfonyl)-7-Phenethyl-7,8-Dihydro-1,6-Naphthyridine-6(5H)-Carboxylate

[0351] Weigh tert-Butyl 2-(Benzylthio)-7-Phenethyl-7,8-Dihydro-1,6-Naphthyridine-6(5H)-Carboxylate (200 mg) into a dry reaction flask, dissolve it in acetonitrile, and then add 1,3-Dichloro-5,5-Dimethylhydantoin (180 mg), Glacial Acetic Acid (110 mg), and Purified Water (66 mg) in sequence. React the mixture at room temperature for 2 hours, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness to obtain the title compound (200 mg).

[0352]

[0353] MS(ESI) m / z (M+H) + = 437.1

[0354] (12) Preparation of Sodium 6-(tert-Butoxycarbonyl)-7-Phenethyl-5,6,7,8-Tetrahydro-1,6-Naphthyridine-2-Sulfonate

[0355] Weigh (2-(chlorosulfonyl)-7-phenethyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (200 mg), dissolve it in tetrahydrofuran (5 mL) and water (5 mL), add sodium hydroxide (22 mg), heat to 80 °C and stir for 1 hour, then remove the solvent under reduced pressure. Purify by column chromatography to obtain the title compound (10 mg).

[0356]

[0357] MS(ESI) m / z (M + H) + = 419.1

[0358] (12) Preparation of 7-phenethyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0359] Weigh sodium 6-(tert-butoxycarbonyl)-7-phenethyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate (10 mg) and dissolve it in water (5 mL), add dilute hydrochloric acid (0.5 M, 5 mL). React at room temperature for 1 hour, concentrate the reaction solution to dryness, and separate by pre-HPLC to obtain the title compound (2.0 mg).

[0360]

[0361] MS(ESI) m / z (M + H) + = 319.0

[0362] 1 H NMR (400 MHz, D2O) δ 7.73 (dd, J = 7.6, 3.8 Hz, 1H), 7.70–7.65 (m, 1H), 7.31–7.23 (m, 4H), 7.18 (t, J = 6.9 Hz, 1H), 4.39 (q, J = 16.4 Hz, 2H), 3.59 (dd, J = 10.9, 7.8 Hz, 1H), 3.38 (dd, J = 18.1, 4.4 Hz, 1H), 3.07 (dd, J = 18.0, 11.0 Hz, 1H), 2.85–2.69 (m, 2H), 2.18–2.08 (m, 1H), 2.03 (dt, J = 13.7, 7.0 Hz, 1H).

[0363] Example 9 Preparation of 7-isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0364]

[0365] (1) Preparation of 2-methyl-N-(2-methylpropylidene)propane-2-sulfinamide

[0366] Weigh 2-methylpropanal (7.3 mL) and dissolve it in dichloromethane (100 mL). Then successively add tert-butanesulfinamide (10.7 g), anhydrous magnesium sulfate (48.28 g), and pyridinium 4-methylbenzenesulfonate (1 g). Heat the mixture to 40 °C and react for 24 hours. Cool it to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify it by column chromatography to obtain the title compound (6.6 g).

[0367]

[0368] MS(ESI) m / z(M+H) + = 176.1

[0369] (2) Preparation of N-[1-(3-bromo-6-methoxypyridin-2-yl)-3-methylbutan-2-yl]-2-methylpropane-2-sulfinamide

[0370] Weigh 3-bromo-6-methoxy-2-methylpyridine (7 g) into a dry reaction flask, inject anhydrous tetrahydrofuran (80 mL) under a nitrogen atmosphere, cool the temperature to -78 °C, and dropwise add a tetrahydrofuran solution of lithium diisopropylamide (18.85 mL, 2.0 M). React at -78 °C for 40 minutes. Dropwise add a solution of 2-methyl-N-(2-methylpropylidene)propane-2-sulfinamide (6.6 g) in tetrahydrofuran (20 mL), react at -78 °C for 30 minutes, and slowly warm to room temperature. Detect the completion of the reaction by LC-MS, quench with saturated ammonium chloride solution, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness.

[0371] Purify it by column chromatography to obtain the title compound (7.5 g).

[0372]

[0373] MS(ESI) m / z(M+H) + = 377.1

[0374] (3) Preparation of ethyl 6-methoxy-2-{3-methyl-2-[(2-methylpropan-2-ylsulfinyl)amino]butyl}pyridine-3-carboxylate

[0375] Weigh N-[1-(3-bromo-6-methoxypyridin-2-yl)-3-methylbutan-2-yl]-2-methylpropane-2-sulfinamide (7.5 g) and dissolve it in ethanol (120 mL). Add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (3.26 g) and N,N-diisopropylethylamine (6.6 ml). After adding, replace the gas in the system with carbon monoxide and react under a carbon monoxide atmosphere by heating to reflux for 12 hours. Remove the solvent under reduced pressure. Purify it by column chromatography to obtain the title compound (6.5 g).

[0376]

[0377] MS(ESI) m / z (M+H) + = 371.1

[0378] (4) Preparation of 2-methoxy-7-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one

[0379] Weigh ethyl 6-methoxy-2-{3-methyl-2-[(2-methylpropan-2-ylsulfinyl)amino]butyl}pyridine-3-carboxylate (6.5 g) and dissolve it in acetonitrile (100 mL). Add cesium carbonate (18 g). Heat up to 80 °C and react for 12 hours. Monitor the reaction by LC-MS until completion. Cool to room temperature, filter by suction. Wash the filter cake with dichloromethane. Concentrate the filtrate to dryness and purify by column chromatography to obtain the title compound (3.1 g).

[0380]

[0381] MS(ESI) m / z (M+H) + = 221.1

[0382] (5) Preparation of 2-hydroxy-7-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one

[0383] Weigh 2-methoxy-7-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one (3 g) and dissolve it in an acetic acid solution of hydrobromic acid (10 mL). Stir at 80 °C for 2 hours. Concentrate the system, triturate with ethyl acetate, filter by suction, and dry the filter cake to obtain the title compound (4 g).

[0384]

[0385] MS(ESI) m / z (M+H) + = 207.1

[0386] (6) Preparation of 2-chloro-7-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one

[0387] Weigh 2-hydroxy-7-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one (4 g), add phosphorus oxychloride (20 mL), heat up to 100 °C and stir for 2 hours. Remove the solvent under reduced pressure, add ethyl acetate, adjust the pH to 9 - 10 with sodium carbonate solution, extract with ethyl acetate, concentrate the organic phase, and purify by column chromatography to obtain the title compound (2.2 g).

[0388]

[0389] MS(ESI) m / z (M+H) + = 225.1

[0390] (7) Preparation of tert-butyl 2-chloro-5-oxo-7-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

[0391] Weigh 2-chloro-7-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one (2.2 g) and dissolve it in dichloromethane (100 mL). Add di-tert-butyl dicarbonate (6.88 mL), triethylamine (11 mL), and 4-dimethylaminopyridine (0.244 g). Heat the mixture to 40 °C and stir overnight. Add water to the system and extract with dichloromethane three times. Dry the organic phase, concentrate it, and purify it by column chromatography to obtain the title compound (3 g).

[0392]

[0393] MS(ESI) m / z (M+H) + = 325.1

[0394] (8) Preparation of tert-butyl 2-chloro-7-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

[0395] Weigh tert-butyl 2-chloro-5-oxo-7-(propan-2-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate (3 g) and dissolve it in dry tetrahydrofuran (40 mL). Replace the air with nitrogen three times and then dropwise add 2 M borane dimethyl sulfide solution. After the addition, heat the mixture to 50 °C and react for 4 hours. Concentrate the reaction mixture under reduced pressure until dry, and purify it by column chromatography to obtain the title compound (1.3 g).

[0396]

[0397] MS(ESI) m / z (M+H) + = 310.1

[0398] (9) Preparation of tert-butyl 2-(benzylthio)-7-isopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0399] Weigh tert-butyl 2-chloro-7-isopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (110 mg) and dissolve it in 1,4-dioxane (10 mL). Add tris(dibenzylideneacetone)dipalladium(0) (32.4 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (41 mg), triethylamine (71.5 mg), and benzyl mercaptan (66 mg) in sequence. Heat the mixture to 115 °C under a nitrogen atmosphere and react overnight. Concentrate the reaction mixture under vacuum and purify it by column chromatography to obtain the title compound (150 mg).

[0400]

[0401] MS(ESI) m / z (M+H) + = 399.2

[0402] (10) Preparation of tert-butyl 2-(chlorosulfonyl)-7-isopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0403] Weigh 2-(benzylthio)-7-isopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (150 mg) into a dry reaction flask, dissolve it with acetonitrile, then successively add 1,3-dichloro-5,5-dimethylhydantoin (148 mg), glacial acetic acid (90 mg), and pure water (54 mg), react at room temperature for 2 hours, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness to obtain the crude title compound (40 mg).

[0404]

[0405] MS(ESI) m / z (M+H) + = 375.1

[0406] (11) Preparation of sodium 6-(tert-butoxycarbonyl)-7-isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0407] Weigh (2-(chlorosulfonyl)-7-isopropyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (40 mg), dissolve it in acetonitrile (5 mL) and water (5 mL), add sodium hydroxide (22 mg), after adding, heat to 80 °C and stir for 1 hour, and remove the solvent under reduced pressure. Purify by column chromatography to obtain the title compound (10 mg).

[0408]

[0409] MS(ESI) m / z (M+H) + = 357.1

[0410] (12) Preparation of 7-isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0411] Weigh sodium 6-(tert-butoxycarbonyl)-7-isopropyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate (10 mg) and dissolve it in water (5 mL), add dilute hydrochloric acid (0.5 M 5 mL). React at room temperature for 1 hour, concentrate the reaction solution to dryness, and separate by pre-HPLC to obtain the title compound (2.0 mg).

[0412]

[0413] MS(ESI) m / z (M+H) + = 257.0

[0414] 1 H NMR (400 MHz, D2O) δ 8.24 (dd, J = 8.0, 2.5 Hz, 1H), 7.99 (t, J = 7.6 Hz, 1H), 4.60 (t, J = 11.0 Hz, 2H), 3.59 (dt, J = 11.7, 4.9 Hz, 1H), 3.48 (dd, J = 18.5, 4.5 Hz, 1H), 3.26 (dd, J = 18.5, 11.9 Hz, 1H), 2.15 (dq, J = 13.5, 6.8 Hz, 1H), 1.06–0.97 (m, 6H).

[0415] Example 10 Preparation of 7-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0416]

[0417] (1) Preparation of 2-methyl-N-(4-butylidene)propane-2-sulfinamide

[0418] Weigh butyraldehyde (10 g) and dissolve it in dichloromethane (100 mL). Then successively add tert-butylsulfinamide (20 g), anhydrous magnesium sulfate (83.3 g) and pyridinium 4-methylbenzenesulfonate (1.74 g). Heat to 40 °C and react for 24 hours. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (22.4 g).

[0419]

[0420] MS(ESI) m / z (M+H) + = 176.1

[0421] (2) Preparation of N-(1-(3-bromo-6-methoxypyridin-2-yl)-5-butane-2-yl)-2-methylpropane-2-sulfinamide

[0422] Weigh 3-bromo-6-methoxy-2-methylpyridine (10 g) into a dry reaction flask, inject anhydrous tetrahydrofuran (80 mL) under a nitrogen atmosphere, and cool the temperature to -78 °C. Dropwise add a tetrahydrofuran solution of lithium diisopropylamide (27.2 mL, 2.0 M), and react at -78 °C for 40 minutes. Dropwise add tetrahydrofuran (20 mL) containing 2-methyl-N-(4-butylidene)propane-2-sulfinamide (9.53 g), react at -30 °C for 30 minutes, and slowly warm to room temperature. Detect that the reaction is complete by LC-MS, add saturated ammonium chloride solution to quench, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness. Purify by column chromatography to obtain the title compound (6.4 g).

[0423]

[0424] MS(ESI) m / z(M+H) + = 377.1

[0425] (3) Preparation of ethyl 2-(2-((tert-butylsulfinyl)amino)-5-butyl)-6-methoxynicotinate

[0426] Weigh (N-(1-(3-bromo-6-methoxypyridin-2-yl)-5-butan-2-yl)-2-methylpropane-2-sulfinamide (6.4 g), dissolve it in ethanol (80 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (2.48 g) and N,N-diisopropylethylamine (5.6 ml). After adding, exchange the gas in the system with carbon monoxide and stir overnight under reflux conditions in a carbon monoxide atmosphere, and remove the solvent under reduced pressure. Purify by column chromatography to obtain the title compound (4 g).

[0427]

[0428] MS(ESI) m / z(M+H) + = 371.1

[0429] (4) Preparation of 2-methoxy-7-(3-propyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0430] Weigh ethyl 2-(2-((tert-butylsulfinyl)amino)-5-butyl)-6-methoxynicotinate (4 g) and dissolve it in acetonitrile (100 mL), add cesium carbonate (17.6 g). Heat to 80 °C and stir overnight, monitor the reaction by LC-MS until completion. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (2.55 g).

[0431]

[0432] MS(ESI) m / z (M+H) + = 221.1

[0433] (5) Preparation of 2-methoxy-7-(3-propyl)-5,6,7,8-tetrahydro-1,6-naphthyridine

[0434] Weigh 2-methoxy-7-(3-propyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (2.55 g) and dissolve it in tetrahydrofuran (100 mL). Under an ice bath, add lithium aluminum hydride (2.6 g), and stir for 8 hours under reflux conditions. Under an ice bath, sequentially add water (2.6 mL), sodium hydroxide solution (15%, 2.6 mL), and water (7.8 mL). After addition, stir at room temperature for 20 minutes, dry with anhydrous magnesium sulfate, filter by suction, wash the filter cake with dichloromethane, and concentrate under reduced pressure to dryness. Purify by column chromatography to obtain the title compound (1.9 g).

[0435]

[0436] MS(ESI) m / z (M+H) + = 207.1

[0437] (6) Preparation of 7-(3-propyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ol

[0438] Weigh 2-methoxy-7-(3-propyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (1.9 g), add acetic acid solution of hydrobromic acid (5 mL), heat to 80 °C and stir for 5 hours. Remove the solvent under reduced pressure, add ethyl acetate for pulping, filter, and dry to obtain the crude product of the title compound (1.5 g).

[0439]

[0440] MS(ESI) m / z (M+H) + = 193.1

[0441] (7) Preparation of 2-chloro-7-(3-propyl)-5,6,7,8-tetrahydro-1,6-naphthyridine

[0442] Weigh 7-(3-propyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ol (0.5 g), add phosphorus oxychloride (10 mL), heat to 100 °C and stir for 4 hours. Remove the solvent under reduced pressure, add ice water and dichloromethane, adjust the pH = 9 - 10 with aqueous Na2CO3 solution, perform liquid-liquid extraction, and concentrate the organic phase to dryness to obtain the crude product of the title compound (0.6 g).

[0443]

[0444] MS(ESI) m / z (M+H) + = 211.1

[0445] (8) Preparation of tert-butyl 2-chloro-7-(3-propyl)-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate

[0446] Weigh 2-chloro-7-(3-propyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (0.6 g), dissolve it in dichloromethane (10 ml) and water (10 ml), add sodium carbonate to adjust the pH to 8 - 9, and add di-tert-butyl dicarbonate (1.29 mL). Stir at room temperature for 1 hour, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the title compound (0.5 g).

[0447]

[0448] MS(ESI) m / z (M+H) + = 311.1

[0449] (9) Preparation of tert-butyl 2-(benzylthio)-7-(3-propyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0450] Weigh tert-butyl 2-chloro-7-(3-propyl)-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate (93 mg), benzyl mercaptan (56 mg), tris(dibenzylideneacetone)dipalladium(0) (28 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg) and triethylamine (163 μL) into a reaction flask, add 1,4-dioxane (5 mL), displace with nitrogen, react at 100 °C overnight, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the title compound (51 mg).

[0451]

[0452] MS(ESI) m / z (M+H) + = 399.2

[0453] (10) Preparation of tert-butyl 2-(chlorosulfonyl)-7-(3-propyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0454] Weigh tert-butyl 2-(benzylthio)-7-(3-propyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (151 mg), dissolve it in acetonitrile (5 mL), and successively add acetic acid (31 mg), water (18 mg) and 1,3-dichloro-5,5-dimethylhydantoin (50 mg) under an ice bath. Stir under an ice bath for 1 hour, add ice water and dichloromethane, perform liquid-liquid extraction, and concentrate the organic phase to dryness to obtain the title compound (45 mg).

[0455]

[0456] MS(ESI) m / z (M+H) + = 375.1

[0457] (11) Preparation of Sodium 6-(tert-Butoxycarbonyl)-7-(3-propyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0458] Weigh 2-(Chlorosulfonyl)-7-(3-propyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (45 mg), dissolve it in tetrahydrofuran (5 mL) and water (5 mL), add sodium hydroxide (15 mg), stir at 80 °C for 1 hour, add ethyl acetate and water, separate by liquid-liquid extraction, discard the organic phase, and concentrate the aqueous phase to dryness to obtain the title compound (40 mg).

[0459]

[0460] MS(ESI) m / z (M+H) + = 357.1

[0461] (12) Preparation of 7-Propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0462] Take sodium 6-(tert-Butoxycarbonyl)-7-(3-propyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate (60 mg), dissolve it in 6M hydrochloric acid solution (3 mL), stir at room temperature for 1 hour, concentrate the system to dryness, and separate by pre-HPLC to obtain the title compound (6.45 mg).

[0463]

[0464] MS(ESI) m / z (M+H) + = 257.0

[0465] 1 H NMR (400 MHz, D2O) δ 7.64–7.47 (m, 2H), 3.93 (s, 2H), 3.06–2.85 (m, 2H), 2.54 (dd, J = 17.4, 10.5 Hz, 1H), 1.53–1.37 (m, 2H), 1.32 (dd, J = 14.8, 7.4 Hz, 2H), 0.80 (t, J = 7.3 Hz, 3H).

[0466] Example 11 Preparation of 7-(3,3-Dimethylbutyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0467]

[0468] (1) Preparation of 4,4-dimethylpentanal

[0469] Weigh (methoxymethyl)triphenylphosphonium chloride (28.3 g) and dissolve it in tetrahydrofuran (150 mL). Add sodium hydride (4.4 g) portionwise under an ice bath and stir at room temperature for 1 hour. Dropwise add a solution of 3,3-dimethylbutanal (5.5 g) in tetrahydrofuran (50 mL) under an ice bath. After the addition is complete, stir overnight at room temperature. Add ice water, perform liquid-liquid extraction. Add dilute hydrochloric acid (27.5 mL, 4.0 M) to the organic phase and stir at room temperature for 1 hour. Add water, perform liquid-liquid extraction and washing, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound (5.0 g).

[0470]

[0471] (2) Preparation of N-(4,4-dimethylpentylidene)-2-methylpropane-2-sulfinamide

[0472] Dissolve 4,4-dimethylpentanal (10.0 g) in tetrahydrofuran (250 mL). Sequentially add tert-butanesulfinamide (8.00 g) and tetraethyl orthotitanate (25.08 g). Heat to 40 °C and react for 24 hours. Quench the reaction by adding saturated brine, perform suction filtration, wash with ethyl acetate. Concentrate the filtrate to dryness. Purify by column chromatography to obtain the title compound (8.01 g).

[0473]

[0474] MS(ESI) m / z (M+H) + = 218.1.

[0475] (3) Preparation of N-(1-(3-bromo-6-methoxypyridin-2-yl)-5,5-dimethylhexan-2-yl)-2-methylpropane-2-sulfinamide

[0476] Weigh 3-bromo-6-methoxy-2-methylpyridine (4.85 g) into a dry reaction flask. Inject anhydrous tetrahydrofuran (40 mL) under a nitrogen atmosphere and cool to -78 °C. Dropwise add a solution of lithium diisopropylamide in tetrahydrofuran (22 mL, 2.0 M) and react at -78 °C for 40 minutes. Dropwise add a solution of N-(4,4-dimethylpentylidene)-2-methylpropane-2-sulfinamide (8.93 g) in tetrahydrofuran (40 mL) and react at -30 °C for 30 minutes. Slowly warm to room temperature. Detect the completion of the reaction by LC-MS, quench by adding saturated ammonium chloride solution, add ethyl acetate and water, perform liquid-liquid separation and extraction. Concentrate the organic phase to dryness. Purify by column chromatography to obtain the title compound (7.92 g).

[0477]

[0478] MS(ESI) m / z (M+H) + = 419.1, 421.1。

[0479] (4) Preparation of ethyl 2-(2-(((tert-butylsulfinyl)amino)amino)-5,5-dimethylhexyl)-6-methoxynicotinate

[0480] Weigh N-(1-(3-bromo-6-methoxypyridin-2-yl)-5,5-dimethylhexan-2-yl)-2-methylpropane-2-sulfinamide (7.92 g), dissolve it in ethanol (150 mL), add [1,1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloride dichloromethane complex (1.56 g) and N,N-diisopropylethylamine (4.88 g). After adding, the system is purged with carbon monoxide and stirred under a carbon monoxide atmosphere at 100 °C for 24 hours, and then the solvent is removed under reduced pressure. The title compound (5.70 g) is obtained by purification by column chromatography.

[0481]

[0482] MS(ESI) m / z (M+H) + = 413.1。

[0483] (5) Preparation of 7-(3,3-dimethylbutyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0484] Weigh ethyl 2-(2-(((tert-butylsulfinyl)amino)amino)-5,5-dimethylhexyl)-6-methoxynicotinate (4.70 g) and dissolve it in acetonitrile (120 mL), add cesium carbonate (18.58 g). Heat to 80 °C and stir overnight. Monitor the reaction by LC-MS until completion. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and obtain the title compound (2.46 g) by purification by column chromatography.

[0485]

[0486] MS(ESI) m / z (M+H) + = 263.1。

[0487] (6) Preparation of 7-(3,3-dimethylbutyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine

[0488] Weigh 7-(3,3-dimethylbutyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one (2.46 g), dissolve it in tetrahydrofuran (100 mL), and add lithium aluminum hydride (1.43 g) in portions. Heat to 70 °C and stir for 2 hours. Then add water (1.5 mL), 15% sodium hydroxide solution (1.5 mL), and water (4.5 mL) successively. Stir at room temperature for 15 minutes, add anhydrous magnesium sulfate, filter by suction, wash, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (1.47 g).

[0489]

[0490] MS(ESI) m / z (M+H) + = 249.1.

[0491] (7) Preparation of 7-(3,3-dimethylbutyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ol

[0492] Weigh 7-(3,3-dimethylbutyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine (0.84 g), add acetic acid solution of hydrobromic acid (10 mL), heat to 80 °C and stir for 8 hours. Remove the solvent under reduced pressure, add ethyl acetate for pulping, filter, and dry to obtain the title compound (1.06 g).

[0493]

[0494] MS(ESI) m / z (M+H) + = 235.1.

[0495] (8) Preparation of 2-chloro-7-(3,3-dimethylbutyl)-5,6,7,8-tetrahydro-1,6-naphthyridine

[0496] Weigh the crude product of 7-(3,3-dimethylbutyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ol (1.06 g), add phosphorus oxychloride (10 mL), heat to 100 °C and stir for 5 hours. Remove the solvent under reduced pressure, add ice water and dichloromethane, adjust the pH = 9 - 10 with saturated sodium carbonate solution, extract by liquid separation, and concentrate the organic phase to dryness. Obtain the title compound (1.06 g).

[0497]

[0498] MS(ESI) m / z (M+H) + = 253.1.

[0499] (9) Preparation of tert-butyl 2-chloro-7-(3,3-dimethylbutyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0500] Weigh the crude product of 2-chloro-7-(3,3-dimethylbutyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (1.06 g), dissolve it in dichloromethane (25 mL) and water (25 mL), and successively add sodium carbonate (1.79 g) and di-tert-butyl dicarbonate (1.47 g). Stir at room temperature for 1 hour, perform liquid-liquid extraction, concentrate the organic phase to dryness, and purify by column chromatography to obtain the title compound (0.25 g).

[0501]

[0502] MS(ESI) m / z (M+H) + = 353.1

[0503] (10) Preparation of tert-butyl 2-(benzylthio)-7-(3,3-dimethylbutyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0504] Weigh 2-chloro-7-(3,3-dimethylbutyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (105 mg), benzyl mercaptan (118 mg), tris(dibenzylideneacetone)dipalladium(0) (28 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (35 mg) and N,N-diisopropylethylamine (77 mg) into a reaction flask, add 1,4-dioxane (6 mL), displace with nitrogen, react at 100 °C overnight, concentrate under reduced pressure to dryness, and purify by column chromatography to obtain the title compound (97 mg).

[0505]

[0506] MS(ESI) m / z (M+H) + = 441.1

[0507] (11) Preparation of tert-butyl 2-(chlorosulfonyl)-7-(3,3-dimethylbutyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0508] Weigh tert-butyl 2-(benzylthio)-7-(3,3-dimethylbutyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (97 mg), dissolve it in acetonitrile (5 mL), and successively add acetic acid (53 mg), water (32 mg) and 1,3-dichloro-5,5-dimethylhydantoin (87 mg) under ice bath. Stir under ice bath for 1 hour, add ice water and dichloromethane, perform liquid-liquid extraction, and concentrate the organic phase to dryness to obtain the title compound (60 mg).

[0509]

[0510] MS(ESI) m / z (M+H) + = 417.1

[0511] (12) Preparation of Sodium 6-(tert-Butoxycarbonyl)-7-(3,3-dimethylbutyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0512] Weigh 2-(Chlorosulfonyl)-7-(3,3-dimethylbutyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (60 mg), dissolve it in tetrahydrofuran (3 mL) and water (3 mL), add sodium hydroxide (30 mg), stir at 80 °C for 1 hour, add ethyl acetate and water, separate by liquid-liquid extraction, discard the organic phase, and concentrate the aqueous phase to dryness to obtain the title compound (60 mg).

[0513]

[0514] MS(ESI) m / z (M+H) + = 399.1

[0515] (13) Preparation of 7-(3,3-Dimethylbutyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0516] Weigh Sodium 6-(tert-Butoxycarbonyl)-7-(3,3-dimethylbutyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate (60 mg), dissolve it in 6M hydrochloric acid solution (3 mL), stir at room temperature for 1 hour, concentrate the system to dryness, and separate by pre-HPLC to obtain the title compound (5.0 mg).

[0517]

[0518] MS(ESI) m / z (M+H) + = 299.1

[0519] 1 H NMR (400 MHz, Deuterium Oxide) δ 7.80–7.60 (m, 2H), 4.39 (s, 2H), 3.58 (ddd, J = 10.6, 7.5, 5.3 Hz, 1H), 3.23 (dd, J = 18.3, 4.8 Hz, 1H), 2.94 (dd, J = 18.3, 10.7 Hz, 1H), 1.81–1.59 (m, 2H), 1.35–1.12 (m, 2H), 0.77 (s, 9H).

[0520] Example 12 Preparation of 7-Isopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0521]

[0522] (1) Preparation of 2-methyl-N-(4-methylpentan-2-ylidene)propane-2-sulfinamide

[0523] Dissolve 4-methyl-1-pentanol (6.21 mL) in dichloromethane (120 mL). Sequentially add 2-iodoxybenzoic acid (28.00 g), tert-butanesulfinamide (6.67 g), anhydrous magnesium sulfate (30.09 g), and pyridinium 4-methylbenzenesulfonate (0.628 g). Heat to 40 °C and react for 24 hours. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (3.92 g).

[0524]

[0525] MS(ESI) m / z(M + H) + = 204.1

[0526] (2) Preparation of N-(1-(3-bromo-6-methoxypyridin-2-yl)-5-methylhexan-2-yl)-2-methylpropane-2-sulfinamide

[0527] Weigh 3-bromo-6-methoxy-2-methylpyridine (4.68 g) into a dry reaction flask, inject anhydrous tetrahydrofuran (100 mL) under a nitrogen atmosphere, and cool to -78 °C. Dropwise add a tetrahydrofuran solution of lithium diisopropylamide (11.58 mL, 2.0 M), and react at -78 °C for 40 minutes. Dropwise add a solution of 2-methyl-N-(4-methylpentan-2-ylidene)propane-2-sulfinamide (3.92 g) in tetrahydrofuran (20 mL), and react at -30 °C for 30 minutes. Slowly warm to room temperature. Detect by LC-MS that the reaction is complete, quench with saturated ammonium chloride solution, add ethyl acetate and water, separate the layers, extract, concentrate the organic phase to dryness, and purify by column chromatography to obtain the title compound (7.15 g).

[0528]

[0529] MS(ESI) m / z(M + H) + = 405.1, 407.1

[0530] (3) Preparation of ethyl 2-(2-((tert-butylsulfinyl)amino)-5-methylhexyl)-6-methoxynicotinate

[0531] Weigh N-(1-(3-bromo-6-methoxypyridin-2-yl)-5-methylhexan-2-yl)-2-methylpropane-2-sulfinamide (7.14 g), dissolve it in ethanol (100 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (4.32 g) and N,N-diisopropylethylamine (6.84 g). After adding, the system is purged with carbon monoxide and reacted overnight under reflux conditions in a carbon monoxide atmosphere, and then concentrated under reduced pressure. Purify by column chromatography to obtain the title compound (2.63 g).

[0532]

[0533] MS(ESI) m / z (M+H) + = 399.1.

[0534] (4) Preparation of 7-isopentyl-2-methoxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0535] Weigh ethyl 2-(2-((tert-butylsulfinyl)amino)-5-methylhexyl)-6-methoxynicotinate (2.63 g), dissolve it in acetonitrile (50 mL), and add cesium carbonate (8.61 g). Heat to 80 °C and stir overnight. Monitor the reaction by LC-MS until completion. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (1.5 g).

[0536]

[0537] MS(ESI) m / z (M+H) + = 249.1.

[0538] (5) Preparation of 7-isopentyl-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine

[0539] Weigh 7-isopentyl-2-methoxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one (1.463 g), dissolve it in tetrahydrofuran (50 mL), and under an ice bath, add lithium aluminum hydride (0.897 g). Stir at 70 °C for 8 hours. Under an ice bath, sequentially add water (0.9 mL), sodium hydroxide solution (15%, 0.9 mL), and water (2.7 mL). After adding, stir at room temperature for 20 minutes, dry with anhydrous magnesium sulfate, filter by suction, wash the filter cake with dichloromethane, and concentrate under reduced pressure to dryness. Purify by column chromatography to obtain the title compound (0.65 g).

[0540]

[0541] MS(ESI) m / z (M+H) + = 235.1.

[0542] (6) Preparation of 7-isopentyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ol

[0543] Weigh 7-isopentyl-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine (0.63 g), add acetic acid solution of hydrobromic acid (5 mL), heat up to 80 °C and stir for 5 hours, remove the solvent under reduced pressure, add ethyl acetate for pulping, filter, and dry to obtain the crude product of the title compound (0.58 g).

[0544]

[0545] MS(ESI) m / z (M+H) + = 221.1.

[0546] (7) Preparation of 2-chloro-7-isopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine

[0547] Weigh 7-isopentyl-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ol (0.57 g), add phosphorus oxychloride (10 mL), heat up to 100 °C and stir for 4 hours, remove the solvent under reduced pressure, add ice water and dichloromethane, adjust the pH = 9 - 10 with aqueous Na2CO3 solution, perform liquid-liquid extraction, and concentrate the organic phase to dryness to obtain the crude product of the title compound (0.5 g).

[0548]

[0549] MS(ESI) m / z (M+H) + = 239.1.

[0550] (8) Preparation of tert-butyl 2-chloro-7-isopentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0551] Weigh 2-chloro-7-isopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine (0.5 g), dissolve it in dichloromethane (10 ml) and water (10 ml), adjust the pH = 8 - 9 with sodium carbonate solution, add di-tert-butyl dicarbonate (1.29 mL). Stir at room temperature for 1 hour, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the title compound (0.52 g).

[0552]

[0553] MS(ESI) m / z (M+H) + = 339.1.

[0554] (9) Preparation of tert-butyl 2-(benzylthio)-7-isopentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0555] Weigh 2-tert-butyl 7-isopentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (203 mg), benzyl mercaptan (112 mg), tris(dibenzylideneacetone)dipalladium(0) (55 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70 mg) and triethylamine (0.3 mL) into a reaction flask, add 1,4-dioxane (10 mL), displace with nitrogen, react at 100 °C overnight, concentrate under reduced pressure to dryness, and purify by column chromatography to obtain the title compound (164 mg).

[0556]

[0557] MS(ESI) m / z (M+H) + = 427.2

[0558] (10) Preparation of 2-(chlorosulfonyl)-7-isopentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester

[0559] Weigh 2-(benzylthio)-7-isopentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (153 mg), dissolve it in acetonitrile (5 mL), and successively add acetic acid (152 mg), water (93 mg) and 1,3-dichloro-5,5-dimethylhydantoin (56 mg) under ice bath. Stir for 1 hour under ice bath, add ice water and dichloromethane, separate by liquid extraction, and concentrate the organic phase to dryness to obtain the title compound (153 mg).

[0560]

[0561] MS(ESI) m / z (M+H) + = 403.1

[0562] (11) Preparation of sodium 6-(tert-butoxycarbonyl)-7-isopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0563] Weigh 2-(chlorosulfonyl)-7-isopentyl-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (153 mg), dissolve it in tetrahydrofuran (6 mL) and water (6 mL), add sodium hydroxide (45 mg), stir at 80 °C for 1 hour, add ethyl acetate and water, separate by liquid extraction, discard the organic phase, and concentrate the aqueous phase to dryness to obtain the title compound (150 mg).

[0564]

[0565] MS(ESI) m / z (M+H) + = 385.1

[0566] (12) Preparation of 7-Isopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic Acid Hydrochloride

[0567] Weigh 6-(tert-Butoxycarbonyl)-7-isopentyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sodium sulfonate (150 mg) and dissolve it in 6 M hydrochloric acid solution (3 mL). Stir at room temperature for 1 hour, concentrate the system to dryness, and separate by pre-HPLC to obtain the title compound (25 mg).

[0568]

[0569] MS(ESI) m / z(M+H) + = 285.1.

[0570] 1 1H NMR(400 MHz, D2O) δ 7.78 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 4.46 (s, 2H), 3.67 (dd, J = 5.6, 2.3 Hz, 1H), 3.29 (dd, J = 18.3, 4.8 Hz, 1H), 2.99 (dd, J = 18.2, 10.8 Hz, 1H), 1.86–1.69 (m, 2H), 1.61–1.48 (m, 1H), 1.32 (dt, J = 9.0, 7.2 Hz, 2H), 0.84 (d, J = 6.6 Hz, 6H).

[0571] Example 13 Preparation of 7-(4-Methoxyphenethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic Acid Hydrochloride

[0572]

[0573] (1) Preparation of N-(3-(4-Methoxyphenyl)propylidene)-2-methylpropane-2-sulfinamide

[0574] Take 3-(4-Methoxyphenyl)propan-1-ol (4.98 g) and dissolve it in dichloromethane (200 mL). Add 2-iodoxybenzoic acid (16.80 g), tert-butylsulfinamide (4.00 g), anhydrous magnesium sulfate (18.50 g), and pyridinium 4-methylbenzenesulfonate (0.377 g) in sequence. Heat to 40 °C and react for 24 hours. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (3.04 g).

[0575]

[0576] MS(ESI) m / z(M+H) + = 268.1.

[0577] (2) Preparation of N-(1-(3-bromo-6-methoxypyridin-2-yl)-4-(4-methoxyphenyl)butan-2-yl)-2-methylpropane-2-sulfinamide

[0578] Weigh 3-bromo-6-methoxy-2-methylpyridine (2.76 g) into a dry reaction flask, inject anhydrous tetrahydrofuran (100 mL) under a nitrogen atmosphere, and cool to -78 °C. Dropwise add a tetrahydrofuran solution of lithium diisopropylamide (6.84 mL, 2.0 M), and react at -78 °C for 40 minutes. Dropwise add tetrahydrofuran (20 mL) containing N-(3-(4-methoxyphenyl)propylidene)-2-methylpropane-2-sulfinamide (3.04 g), react at -30 °C for 30 minutes, and slowly warm to room temperature. Detect that the reaction is complete by LC-MS, quench with saturated ammonium chloride solution, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness. Purify by column chromatography to obtain the title compound (2.91 g).

[0579]

[0580] MS(ESI) m / z(M+H) + = 469.1, 471.1.

[0581] (3) Preparation of ethyl 2-(2-((tert-butylsulfinyl)amino)-4-(4-methoxyphenyl)butyl)-6-methoxynicotinate

[0582] Weigh N-(1-(3-bromo-6-methoxypyridin-2-yl)-4-(4-methoxyphenyl)butan-2-yl)-2-methylpropane-2-sulfinamide (2.90 g), dissolve it in ethanol (100 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.01 g) and N,N-diisopropylethylamine (1.60 g). After adding, exchange the gas in the system with carbon monoxide and react overnight under reflux conditions in a carbon monoxide atmosphere, and remove the solvent under reduced pressure. Purify by column chromatography to obtain the title compound (1.66 g).

[0583]

[0584] MS(ESI) m / z(M+H) + = 463.2.

[0585] (4) Preparation of 2-methoxy-7-(4-methoxyphenethyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0586] Weigh ethyl 2-(2-((tert-butylsulfinyl)amino)-4-(4-methoxyphenyl)butyl)-6-methoxynicotinate (1.66 g) and dissolve it in acetonitrile (50 mL). Add cesium carbonate (4.69 g). Heat the mixture to 80 °C and stir overnight. Monitor the reaction by LC-MS until completion. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (0.78 g).

[0587]

[0588] MS(ESI) m / z(M+H) + = 313.1.

[0589] (5) Preparation of 2-methoxy-7-(4-methoxyphenethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine

[0590] Weigh 2-methoxy-7-(4-methoxyphenethyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (0.78 g) and dissolve it in tetrahydrofuran (50 mL). Under an ice bath, add lithium aluminum hydride (0.38 g), and stir at 70 °C for 8 hours. Under the ice bath, sequentially add water (0.38 mL), sodium hydroxide solution (15%, 0.38 mL), and water (1.14 mL). After addition, stir at room temperature for 20 minutes, dry with anhydrous magnesium sulfate, filter by suction, wash the filter cake with dichloromethane, and concentrate under reduced pressure to dryness. Purify by column chromatography to obtain the title compound (0.356 g).

[0591]

[0592] MS(ESI) m / z(M+H) + = 299.2.

[0593] (6) Preparation of 2-chloro-7-(4-methoxyphenethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine

[0594] Weigh 2-methoxy-7-(4-methoxyphenethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (0.34 g), add phosphorus oxychloride (5 mL), heat to 100 °C and stir for 10 hours. Remove the solvent under reduced pressure, add ice water and dichloromethane, adjust the pH to 9 - 10 with an aqueous Na2CO3 solution, perform liquid-liquid extraction, and concentrate the organic phase to dryness to obtain the crude title compound (0.3 g).

[0595]

[0596] MS(ESI) m / z(M+H) + = 303.1.

[0597] (7) Preparation of tert-Butyl 2-Chloro-7-(4-methoxyphenethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0598] Weigh 2-chloro-7-(4-methoxyphenethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (0.3 g), dissolve it in dichloromethane (5 ml) and water (5 ml), add sodium carbonate solution to adjust the pH to 8 - 9, and add di-tert-butyl dicarbonate (0.52 mL). Stir at room temperature for 1 hour, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the title compound (0.16 g).

[0599]

[0600] MS(ESI) m / z(M + H) + = 403.1.

[0601] (8) Preparation of tert-Butyl 2-(Benzylthio)-7-(4-methoxyphenethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0602] Weigh tert-butyl 2-chloro-7-(4-methoxyphenethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (80 mg), benzyl mercaptan (137 mg), tris(dibenzylideneacetone)dipalladium(0) (18 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23 mg) and triethylamine (108 μL) into a reaction flask, add 1,4-dioxane (5 mL), displace with nitrogen, react at 100 °C overnight, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the title compound (80 mg).

[0603]

[0604] MS(ESI) m / z(M + H) + = 491.2.

[0605] (9) Preparation of tert-Butyl 2-(Chlorosulfonyl)-7-(4-methoxyphenethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0606] Weigh tert-butyl 2-(benzylthio)-7-(4-methoxyphenethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate (80 mg), dissolve it in acetonitrile (5 mL), and successively add acetic acid (51 mg), water (23 mg) and 1,3-dichloro-5,5-dimethylhydantoin (63 mg) under ice bath. Stir under ice bath for 1 hour, add ice water and dichloromethane, extract by liquid separation, and concentrate the organic phase to dryness to obtain the title compound (81 mg).

[0607]

[0608] MS(ESI) m / z (M+H) + = 467.1

[0609] (10) Preparation of Sodium 6-(tert-Butoxycarbonyl)-7-(4-methoxyphenethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0610] Weigh 2-(Chlorosulfonyl)-7-(4-methoxyphenethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (81 mg), dissolve it in tetrahydrofuran (6 mL) and water (6 mL), add sodium hydroxide (12.8 mg), stir at 80 °C for 1 hour, add ethyl acetate and water, separate and extract by liquid separation, discard the organic phase, and concentrate the aqueous phase to dryness to obtain the title compound (50 mg).

[0611]

[0612] MS(ESI) m / z (M+H) + = 449.1

[0613] (11) Preparation of 7-(4-Methoxyphenethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0614] Weigh sodium 6-(tert-Butoxycarbonyl)-7-(4-methoxyphenethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate (50 mg), dissolve it in 6M hydrochloric acid solution (3 mL), stir at room temperature for 1 hour, concentrate the system to dryness, and separate by pre-HPLC to obtain the title compound (3.26 mg).

[0615]

[0616] MS(ESI) m / z (M+H) + = 349.0

[0617] 1 H NMR (400 MHz, D2O) δ 7.72 (q, J = 8.1 Hz, 2H), 7.20 (d, J = 8.3 Hz, 2H), 6.88 (d, J = 8.3 Hz, 2H), 4.34 (d, J = 9.9 Hz, 2H), 3.72 (s, 3H), 3.51 (s, 1H), 3.27 (dd, J = 18.1, 4.7 Hz, 1H), 2.97 (dd, J = 18.1, 10.8 Hz, 1H), 2.81–2.64 (m, 2H), 2.15–1.92 (m, 2H).

[0618] Example 14 Preparation of 7-(Cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0619]

[0620] (1) Preparation of N-(2-Cyclohexylethylidene)-2-methylpropane-2-sulfinamide

[0621] Weigh 2-cyclohexyl-1-ethanol (5.13 g) and dissolve it in dichloromethane (180 mL). Then successively add tert-butanesulfinamide (5.33 g), 2-iodoxybenzoic acid (22.4 g), anhydrous magnesium sulfate (24.1 g) and pyridinium 4-methylbenzenesulfonate (0.503 g). Heat to 40 °C and react for 24 hours. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (3.8 g).

[0622]

[0623] MS(ESI) m / z(M+H) + = 230.1.

[0624] (2) Preparation of N-[1-(3-Bromo-6-methoxypyridin-2-yl)-3-cyclohexylpropan-2-yl]-2-methylpropane-2-sulfinamide

[0625] Weigh 3-bromo-6-methoxy-2-methylpyridine (4 g) into a dry reaction flask, inject anhydrous tetrahydrofuran (130 mL) under a nitrogen atmosphere, and cool to -78 °C. Dropwise add a tetrahydrofuran solution of lithium diisopropylamide (10 mL, 2.0 M), and react at -78 °C for 40 minutes. Dropwise add tetrahydrofuran (20 mL) containing N-(2-cyclohexylethylidene)-2-methylpropane-2-sulfinamide (3.8 g), and react at -30 °C for 30 minutes. Slowly warm to room temperature. Detect by LC-MS that the reaction is complete, quench with saturated ammonium chloride solution, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness. Purify by column chromatography to obtain the title compound (6.34 g).

[0626]

[0627] MS(ESI) m / z(M+H) + = 431.1.

[0628] (3) Preparation of Ethyl 2-{3-Cyclohexyl-2-[(2-methylpropan-2-sulfinyl)amino]propyl}ethyl-6-methoxypyridine-3-carboxylate

[0629] Weigh: N-[1-(3-bromo-6-methoxypyridin-2-yl)-3-cyclohexylpropan-2-yl]-2-methylpropane-2-sulfinamide (6.34 g), dissolve it in ethanol (100 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (2.41 g) and N,N-diisopropylethylamine (5.24 mL). After adding, the system is purged with carbon monoxide and under a carbon monoxide atmosphere, heated to 100 °C and stirred for 24 hours, then concentrated under reduced pressure. Purify by column chromatography to obtain the title compound (2.5 g).

[0630]

[0631] MS(ESI) m / z (M+H) + = 425.2

[0632] (4) Preparation of 7-(cyclohexylmethyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one

[0633] Weigh ethyl 2-{3-cyclohexyl-2-[(2-methylpropane-2-sulfinyl)amino]propyl}ethyl-6-methoxypyridine-3-carboxylate (2.5 g), dissolve it in acetonitrile (60 mL), and add cesium carbonate (9.61 g). Heat to 80 °C and stir overnight, monitor the reaction by LC-MS until completion. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (1.5 g).

[0634]

[0635] MS(ESI) m / z (M+H) + = 275.1

[0636] (5) Preparation of 7-(cyclohexylmethyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridine

[0637] Weigh 7-(cyclohexylmethyl)-2-methoxy-5,6,7,8-tetrahydro-1,6-naphthyridin-5-one (1.5 g), dissolve it in tetrahydrofuran (100 mL), under an ice bath, add lithium aluminum hydride (0.832 g), stir at 70 °C for 8 hours, under an ice bath, sequentially add water (1 mL), sodium hydroxide solution (15%, 1 mL) and water (3 mL). After adding, stir at room temperature for 20 minutes, dry with anhydrous magnesium sulfate, filter by suction, wash the filter cake with dichloromethane, and concentrate under reduced pressure to dryness. Purify by column chromatography to obtain the title compound (0.65 g).

[0638]

[0639] MS(ESI) m / z (M+H) += 261.1。

[0640] (6) Preparation of 2-chloro-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine

[0641] Weigh 7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ol (0.7 g), add phosphorus oxychloride (10 mL), heat to 100 °C and stir for 10 hours. Remove the solvent under reduced pressure, add ice water and dichloromethane, adjust the pH to 9 - 10 with aqueous Na2CO3 solution, perform liquid-liquid extraction, and concentrate the organic phase to dryness to obtain the crude product of the title compound (0.6 g).

[0642]

[0643] MS(ESI) m / z (M+H) + = 265.1。

[0644] (7) Preparation of tert-butyl 2-chloro-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

[0645] Weigh 2-chloro-7-(4-methoxyphenethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (0.6 g), dissolve it in dichloromethane (5 ml) and water (5 ml), adjust the pH to 8 - 9 with sodium carbonate solution, and add di-tert-butyl dicarbonate (1.1 mL). Stir at room temperature for 1 hour, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the title compound (0.5 g).

[0646]

[0647] MS(ESI) m / z (M+H) + = 365.1。

[0648] (8) Preparation of tert-butyl 2-(benzylthio)-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

[0649] Weigh tert-butyl 2-chloro-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate (200 mg), benzyl mercaptan (136.4 mg), tris(dibenzylideneacetone)dipalladium(0) (50 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (63.58 mg) and triethylamine (0.152 mL) into a reaction flask, add 1,4-dioxane (10 mL), displace with nitrogen, react at 100 °C overnight, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the title compound (65 mg).

[0650]

[0651] MS(ESI) m / z (M+H) + = 453.2

[0652] (9) Preparation of tert-butyl 2-(chlorosulfonyl)-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylate

[0653] Weigh 2-(benzylthio)-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylic acid tert-butyl ester (65 mg), dissolve it in acetonitrile (5 mL), and successively add acetic acid (34.32 mg), water (20.6 mg) and 1,3-dichloro-5,5-dimethylhydantoin (55.2 mg) under ice bath. Stir for 1 hour under ice bath, add ice water and dichloromethane, separate by liquid-liquid extraction, and concentrate the organic phase to dryness to obtain the title compound (60 mg).

[0654]

[0655] MS(ESI) m / z (M+H) + = 429.1

[0656] (10) Preparation of sodium 6-[(tert-butoxy)carbonyl]-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0657] Weigh 2-(chlorosulfonyl)-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carboxylic acid tert-butyl ester (60 mg), dissolve it in tetrahydrofuran (5 mL) and water (5 mL), add sodium hydroxide (17 mg), stir at 80 °C for 1 hour, add ethyl acetate and water, separate by liquid-liquid extraction, discard the organic phase, and concentrate the aqueous phase to dryness to obtain the title compound (50 mg).

[0658]

[0659] MS(ESI) m / z (M+H) + = 411.1

[0660] (11) Preparation of 7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0661] Take sodium 6-[(tert-butoxy)carbonyl]-7-(cyclohexylmethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate (50 mg), dissolve it in 6 M hydrochloric acid solution (3 mL), stir at room temperature for 1 hour, concentrate the system to dryness, and separate by pre-HPLC to obtain the title compound (6.2 mg).

[0662]

[0663] MS(ESI) m / z (M+H)+ = 311.0.

[0664] 1 H NMR (400 MHz, D2O) δ 7.77 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 4.50–4.35 (m, 2H), 3.79 (ddd, J = 16.5, 10.9, 5.8 Hz, 1H), 3.31 (dd, J = 18.3, 4.8 Hz, 1H), 2.95 (dd, J = 18.2, 10.7 Hz, 1H), 1.67–1.44 (m, 8H), 1.22–1.03 (m, 3H), 0.98–0.81 (m, 2H).

[0665] Example 15 Preparation of 7-Cyclohexylethyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic Acid Hydrochloride

[0666]

[0667] (1) Preparation of N-(3-Cyclohexylpropylidene)-2-methylpropane-2-sulfinamide

[0668] Weigh 3-cyclohexylpropan-1-ol (9.0 g) and dissolve it in dichloromethane (200 mL). Then successively add tert-butanesulfinamide (9.2 g), anhydrous magnesium sulfate (48.28 g), and pyridinium 4-methylbenzenesulfonate (794 mg). Heat to 40 °C and react for 24 hours. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (4.4 g).

[0669]

[0670] MS(ESI) m / z (M+H) + = 244.1.

[0671] (2) Preparation of N-(1-(3-Bromo-6-methoxypyridin-2-yl)-4-cyclohexylbutan-2-yl)-2-methylpropane-2-sulfinamide

[0672] Weigh 3-bromo-6-methoxy-2-methylpyridine (4 g) into a dry reaction flask, inject anhydrous tetrahydrofuran (100 mL) under a nitrogen atmosphere, and cool the temperature to -78 °C. Dropwise add a tetrahydrofuran solution of lithium diisopropylamide (10 mL, 2.0 M), and react at -78 °C for 40 minutes. Dropwise add tetrahydrofuran (20 mL) containing N-(3-cyclohexylpropylidene)-2-methylpropane-2-sulfinamide (4.4 g), react at -30 °C for 30 minutes, and slowly warm to room temperature. After detecting the completion of the reaction by LC-MS, quench with saturated ammonium chloride solution, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness. Purify by column chromatography to obtain the title compound (3.68 g).

[0673]

[0674] MS(ESI)m / z(M+H) + = 445.1

[0675] (3) Preparation of ethyl 6-methoxy-2-(2-((tert-butylsulfinyl)amino)-4-cyclohexylbutyl)pyridine-3-carboxylate

[0676] Weigh: N-(1-(3-bromo-6-methoxypyridin-2-yl)-4-cyclohexylbutan-2-yl)-2-methylpropane-2-sulfinamide (3.68 g), dissolve it in ethanol (100 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (1.35 g) and N,N-diisopropylethylamine (2.7 ml). After adding, replace the gas in the system with carbon monoxide and react overnight under reflux conditions in a carbon monoxide atmosphere, and remove the solvent under reduced pressure. Purify by column chromatography to obtain the title compound (2.18 g).

[0677]

[0678] MS(ESI)m / z(M+H) + = 439.2

[0679] (4) Preparation of 6-(tert-butylsulfinyl)-7-(2-cyclohexylethyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0680] Weigh ethyl 6-methoxy-2-(2-((tert-butylsulfinyl)amino)-4-cyclohexylbutyl)pyridine-3-carboxylate (2.18 g) and dissolve it in acetonitrile (40 mL), add cesium carbonate (3.22 g). Heat to 80 °C and stir overnight, monitor the reaction by LC-MS until completion. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (1.3 g).

[0681]

[0682] MS(ESI) m / z (M+H) + = 393.1

[0683] (5) Preparation of 7-(2-cyclohexylethyl)-2-hydroxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0684] Weigh 6-(tert-butylsulfinyl)-7-(2-cyclohexylethyl)-2-methoxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one (1.3 g), dissolve it in acetic acid solution of hydrobromic acid (15 mL), stir at 80 °C for 8 hours, concentrate the system, slurry with ethyl acetate, filter by suction, and dry the filter cake to obtain the title compound (1.0 g).

[0685]

[0686] MS(ESI) m / z (M+H) + = 275.1

[0687] (6) Preparation of 2-chloro-7-(2-cyclohexylethyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0688] Weigh 7-(2-cyclohexylethyl)-2-hydroxy-7,8-dihydro-1,6-naphthyridin-5(6H)-one (1.0 g), add phosphorus oxychloride (20 mL), heat up to 100 °C and stir for 10 hours, remove the solvent under reduced pressure, add ethyl acetate, adjust the pH = 9 - 10 with sodium carbonate solution, extract with ethyl acetate, concentrate the organic phase, and purify and separate by silica gel column to obtain the title compound (600 mg).

[0689]

[0690] MS(ESI) m / z (M+H) + = 293.1

[0691] (7) Preparation of tert-butyl 2-chloro-7-(2-cyclohexylethyl)-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0692] Weigh 2-chloro-7-(2-cyclohexylethyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (600 mg) and dissolve it in dichloromethane (20 mL), add di-tert-butyl dicarbonate (2.1 mL), triethylamine (2.5 mL), 4-dimethylaminopyridine (40 mg), heat up to 40 °C and react overnight, add water and dichloromethane to the system for extraction 3 times, dry and concentrate the organic phase, and purify and separate by silica gel column to obtain the title compound (600 mg).

[0693]

[0694] MS(ESI) m / z (M+H) + = 393.1

[0695] (8) Preparation of tert-butyl 2-chloro-7-(2-cyclohexylethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0696] Weigh 2-chloro-7-(2-cyclohexylethyl)-5-oxo-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (600 mg) and dissolve it in dry tetrahydrofuran (10 mL). After displacing the air with nitrogen three times, add dropwise 2M borane dimethyl sulfide solution (10.0 equivalents). After the addition, heat the reaction to 60 °C and react for 3 hours. Then cool to room temperature, slowly add dropwise methanol to quench the reaction until no bubbles are generated, and then stir at 60 °C for 2 hours. Concentrate under reduced pressure to dryness and purify by column chromatography to obtain the title compound (300 mg).

[0697]

[0698] MS(ESI) m / z (M+H) + = 379.1

[0699] (9) Preparation of tert-butyl 2-(benzylthio)-7-(2-cyclohexylethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0700] Weigh 2-chloro-7-(2-cyclohexylethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (200 mg), di-tert-butyl phosphate (131 mg), tris(dibenzylideneacetone)dipalladium (97 mg), 1,1'-bis(diphenylphosphino)ferrocene (122 mg) and triethylamine (0.13 mL) into a reaction flask, add 1,4-dioxane (10 mL), displace the air with nitrogen, and react at 115 °C overnight. Concentrate under reduced pressure to dryness and purify by TLC preparation to obtain the title compound (170 mg).

[0701]

[0702] MS(ESI) m / z (M+H) + = 467.2

[0703] (10) Preparation of tert-butyl 2-(chlorosulfonyl)-7-(2-cyclohexylethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0704] Weigh 2-(benzylthio)-7-(2-cyclohexylethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (170 mg) into a dry reaction flask, dissolve it with acetonitrile, then successively add 1,3-dichloro-5,5-dimethylhydantoin (102 mg), glacial acetic acid (88 mg), and purified water (118 mg), react at 0 °C for 1 hour, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness to obtain the title compound (90 mg).

[0705]

[0706] MS(ESI) m / z(M+H) + = 443.1.

[0707] (11) Preparation of sodium 6-(tert-butoxycarbonyl)-7-(2-cyclohexylethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0708] Weigh 2-(chlorosulfonyl)-7-(2-cyclohexylethyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (90 mg), dissolve it in tetrahydrofuran (5 mL) and water (5 mL), add sodium hydroxide (40 mg), after adding, heat to 80 °C and stir for 1 hour, and remove the solvent under reduced pressure. Purify by column chromatography to obtain the title compound (20 mg).

[0709]

[0710] MS(ESI) m / z(M - 22 + H) + = 425.1.

[0711] (12) Preparation of 7-cyclohexylethyl-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0712] Weigh sodium 6-(tert-butoxycarbonyl)-7-(2-cyclohexylethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate (20 mg) and dissolve it in water (5 mL), add dilute hydrochloric acid (0.5 M, 5 mL). React at room temperature for 1 hour, concentrate the reaction solution to dryness, and separate by pre-HPLC to obtain the title compound (7.0 mg).

[0713]

[0714] MS(ESI) m / z(M + H) + = 325.0.

[0715] 11H NMR (400 MHz, DMSO) δ 10.38 (s, 1H), 8.31 (d, J = 8.1 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 4.44 (dd, J = 36.0, 16.8 Hz, 2H), 3.58 (d, J = 6.6 Hz, 1H), 3.46 (dd, J = 18.3, 4.1 Hz, 1H), 3.20–3.10 (m, 1H), 1.96 (d, J = 4.9 Hz, 1H), 1.75–1.56 (m, 6H), 1.31–1.09 (m, 7H), 0.87 (dd, J = 18.7, 7.7 Hz, 2H).

[0716] Example 16 Preparation of 7-(3-Phenylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic Acid Hydrochloride

[0717]

[0718] (1) Preparation of 2-Methyl-N-(4-phenylbutylidene)propane-2-sulfinamide

[0719] Dissolve 4-phenylbutanol (7.6 mL) in dichloromethane (200 mL), and successively add 2-iodoxybenzoic acid (28.00 g), tert-butylsulfinamide (9.07 g), anhydrous magnesium sulfate (30.80 g), and pyridinium 4-methylbenzenesulfonate (0.627 g). Heat to 40 °C and react for 24 hours. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (5.1 g).

[0720]

[0721] MS (ESI) m / z (M+H) + = 252.1.

[0722] (2) Preparation of N-(1-(3-Bromo-6-methoxypyridin-2-yl)-5-phenylpentan-2-yl)-2-methylpropane-2-sulfinamide

[0723] Weigh 3-bromo-6-methoxy-2-methylpyridine (4.85 g) into a dry reaction flask, inject anhydrous tetrahydrofuran (100 mL) under a nitrogen atmosphere, and cool the temperature to -78 °C. Dropwise add a tetrahydrofuran solution of lithium diisopropylamide (12.00 mL, 2.0 M), and react at -78 °C for 40 minutes. Dropwise add tetrahydrofuran (20 mL) containing 2-methyl-N-(4-phenylbutylidene)propane-2-sulfinamide (5.02 g), react at -30 °C for 30 minutes, and slowly warm to room temperature. After detecting the completion of the reaction by LC-MS, quench with saturated ammonium chloride solution, add ethyl acetate and water, separate the layers, extract, and concentrate the organic phase to dryness.

[0724] Purify by column chromatography to obtain the title compound (7.15 g).

[0725]

[0726] MS(ESI) m / z(M+H) + = 453.1, 455.1.

[0727] (3) Preparation of ethyl 2-(2-((tert-butylsulfinyl)amino)-5-phenylpentyl)-6-methoxynicotinate

[0728] Weigh N-(1-(3-bromo-6-methoxypyridin-2-yl)-5-phenylpentan-2-yl)-2-methylpropane-2-sulfinamide (5.42 g), dissolve it in ethanol (150 mL), add [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.979 g) and N,N-diisopropylethylamine (4.12 mL). After adding, exchange the gas in the system with carbon monoxide and react overnight under reflux conditions in a carbon monoxide atmosphere, and remove the solvent under reduced pressure. Purify by column chromatography to obtain the title compound (2.01 g).

[0729]

[0730] MS(ESI) m / z(M+H) + = 447.2.

[0731] (4) Preparation of 2-methoxy-7-(3-phenylpropyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one

[0732] Weigh ethyl 2-(2-((tert-butylsulfinyl)amino)-5-phenylpentyl)-6-methoxynicotinate (2.00 g) and dissolve it in acetonitrile (50 mL), add cesium carbonate (5.87 g). Heat to 80 °C and stir overnight, monitor the reaction by LC-MS until completion. Cool to room temperature, filter by suction, wash the filter cake with dichloromethane, concentrate the filtrate to dryness, and purify by column chromatography to obtain the title compound (1.1 g).

[0733]

[0734] MS(ESI) m / z (M+H) + = 297.1

[0735] (5) Preparation of 2-Methoxy-7-(3-phenylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine

[0736] Weigh 2-methoxy-7-(3-phenylpropyl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (1.10 g) and dissolve it in tetrahydrofuran (70 mL). Under an ice bath, add lithium aluminum hydride (0.562 g), and stir at 70 °C for 8 hours. Monitor the reaction by LC-MS until completion. Under an ice bath, sequentially add water (0.56 mL), sodium hydroxide solution (15%, 0.56 mL), and water (1.68 mL). After addition, stir at room temperature for 20 minutes, dry with anhydrous magnesium sulfate, filter by suction, wash the filter cake with dichloromethane, and concentrate under reduced pressure to dryness. Purify by column chromatography to obtain the title compound (0.41 g).

[0737]

[0738] MS(ESI) m / z (M+H) + = 283.2

[0739] (6) Preparation of 7-(3-Phenylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ol

[0740] Weigh 2-methoxy-7-(3-phenylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (0.40 g), add acetic acid solution of hydrobromic acid (5 mL), heat to 80 °C and stir for 5 hours. Remove the solvent under reduced pressure, add ethyl acetate for pulping, filter, and dry to obtain the title compound (0.295 g).

[0741]

[0742] MS(ESI) m / z (M+H) + = 269.1

[0743] (7) Preparation of 2-Chloro-7-(3-phenylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine

[0744] Weigh 7-(3-phenylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridin-2-ol (0.29 g), add phosphorus oxychloride (6 mL), heat to 100 °C and stir for 10 hours. Remove the solvent under reduced pressure, add ice water and dichloromethane, adjust the pH to 9 - 10 with aqueous Na2CO3 solution, perform liquid-liquid extraction, and concentrate the organic phase to dryness to obtain the crude title compound (0.6 g).

[0745]

[0746] MS(ESI) m / z (M+H) + = 287.1

[0747] (8) Preparation of tert-butyl 2-chloro-7-(3-phenylpropyl)-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate

[0748] Weigh 2-chloro-7-(4-methoxyphenethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (0.6 g), dissolve it in dichloromethane (5 ml) and water (5 ml), add sodium carbonate solution to adjust the pH = 8 - 9, and add di-tert-butyl dicarbonate (0.50 mL). Stir at room temperature for 1 hour, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the title compound (0.22 g).

[0749]

[0750] MS(ESI) m / z (M+H) + = 387.1

[0751] (9) Preparation of tert-butyl 2-(benzylthio)-7-(3-phenylpropyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0752] Weigh tert-butyl 2-chloro-7-(3-phenylpropyl)-7,8-dihydro-1,6-naphthyridine-6-(5H)-carboxylate (147 mg), benzyl mercaptan (71 mg), tris(dibenzylideneacetone)dipalladium(0) (35 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (44 mg) and triethylamine (113 μL) into a reaction flask, add 1,4-dioxane (5 mL), displace with nitrogen, react at 100 °C overnight, concentrate to dryness under reduced pressure, and purify by column chromatography to obtain the title compound (159 mg).

[0753]

[0754] MS(ESI) m / z (M+H) + = 475.2

[0755] (10) Preparation of tert-butyl 2-(chlorosulfonyl)-7-(3-phenylpropyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylate

[0756] Weigh 2-(benzylthio)-7-(3-phenylpropyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (156 mg), dissolve it in acetonitrile (5 mL), and successively add acetic acid (79 mg), water (48 mg), and 1,3-dichloro-5,5-dimethylhydantoin (130 mg) under an ice bath. Stir for 1 hour under an ice bath, add ice water and dichloromethane, perform liquid-liquid extraction, and concentrate the organic phase to dryness to obtain the crude title compound (148 mg).

[0757]

[0758] MS(ESI) m / z(M+H) + = 451.1.

[0759] (11) Preparation of sodium 6-(tert-butoxycarbonyl)-7-(3-phenylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate

[0760] Weigh 2-(chlorosulfonyl)-7-(3-phenylpropyl)-7,8-dihydro-1,6-naphthyridine-6(5H)-carboxylic acid tert-butyl ester (148 mg), dissolve it in tetrahydrofuran (5 mL) and water (5 mL), add sodium hydroxide (27 mg), stir at 80 °C for 1 hour, add ethyl acetate and water, perform liquid-liquid extraction, discard the organic phase, and concentrate the aqueous phase to dryness to obtain the crude title compound (50 mg).

[0761]

[0762] MS(ESI) m / z(M+H) + = 433.1.

[0763] (12) Preparation of 7-(3-phenylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid hydrochloride

[0764] Take the crude product of sodium -(tert-butoxycarbonyl)-7-(3-phenylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonate (50 mg), dissolve it in 6M hydrochloric acid solution (3 mL), stir at room temperature for 1 hour, concentrate the system to dryness, and separate by pre-HPLC to obtain the title compound (2.25 mg).

[0765]

[0766] MS(ESI) m / z(M+H) + = 333.0.

[0767] 11H NMR (400 MHz, D2O) δ 7.74 (dd, J = 18.5, 8.1 Hz, 2H), 7.24 (ddd, J = 21.9, 14.9, 7.3 Hz, 5H), 4.42 (s, 2H), 3.72–3.62 (m, 1H), 3.32–3.22 (m, 1H), 3.01–2.92 (m, 1H), 2.63 (d, J = 3.6 Hz, 2H), 1.83–1.58 (m, 4H). Example 17 Preparation of 1,2,3,4-tetrahydroisoquinoline-6-sulfonic acid hydrochloride

[0768]

[0769] (1) Preparation of tert-butyl 6-(benzylthio)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0770] Weigh 6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (600 mg), benzyl mercaptan (0.34 mL), tris(dibenzylideneacetone)dipalladium (88 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (112 mg) and N,N-diisopropylethylamine (0.64 mL) into a reaction flask, add 1,4-dioxane (10 mL), displace with argon 3 times, react at 90 °C for 6 hours, and TLC shows that the reaction is complete. Quench with water, extract twice with ethyl acetate, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain the title compound (470 mg).

[0771]

[0772] MS (ESI) m / z (M - 55) + = 300.0 / (M - 99) + = 256.0.

[0773] (2) Preparation of tert-butyl 6-(chlorosulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate

[0774] Weigh tert-butyl 6-(benzylthio)-3,4-dihydroisoquinoline-2(1H)-carboxylate (220 mg), dissolve it in acetonitrile (4 mL), and successively add water (90 μL), acetic acid (142 μL) and 1,3-dichloro-5,5-dimethylhydantoin (232 mg) under ice bath, stir under ice bath for 30 minutes, and TLC shows that the reaction is complete. Adjust the pH to 8 - 9 with saturated sodium bicarbonate solution, extract twice with ethyl acetate, wash with saturated brine, dry over anhydrous sodium sulfate, and purify by column chromatography to obtain the title compound (160 mg).

[0775]

[0776] (3) Preparation of Sodium 2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonate

[0777] Weigh 6-(Chlorosulfonyl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (150 mg), dissolve it in tetrahydrofuran (3 mL) and water (3 mL), add sodium hydroxide (54 mg), stir at 100 °C for 2 hours, and TLC shows that the reaction is complete. Concentrate under reduced pressure to obtain the crude title compound (54 mg).

[0778]

[0779] MS(ESI) m / z (M - H) + = 312.0 / (M - 55) + = 258.0 / (M - 99) + = 258.0.

[0780] (4) Preparation of 1,2,3,4-Tetrahydroisoquinoline-6-sulfonic acid hydrochloride

[0781] Weigh sodium 2-(tert-Butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonate (54 mg), suspend it in dichloromethane (3 mL), add 1,4-dioxane hydrochloride (1.5 mL), and react at room temperature for 5 h. LC-MS shows that the reaction is complete. Concentrate the system to dryness and purify by pre-HPLC to obtain the title compound (0.95 mg).

[0782]

[0783] MS(ESI) m / z (M + H) + = 214.0.

[0784] 1 H NMR(400 MHz, Deuterium Oxide) δ 7.55 (d, J = 7.6 Hz, 2H), 7.23 (d, J = 8.2 Hz, 1H), 4.32 (s, 2H), 3.44 (t, J = 6.4 Hz, 2H), 3.07 (t, J = 6.4 Hz, 2H).

[0785] The preparation methods exemplified in the foregoing embodiments are illustrative of the preparation process of the compounds of the present invention. Those skilled in the art can refer to the above specific methods and combine with the general knowledge in the art to prepare other compounds within the scope of the present invention, which is easily achievable for those skilled in the art. At the same time, the salts of the prepared compounds (such as the hydrochloride salt prepared in the foregoing embodiments) can also be converted into free compounds by using conventional experimental means in the art. For example, the following method can be adopted: Take the hydrochloride salt of the compound, dissolve it completely with water, slowly add 20% sodium bicarbonate solution until a large amount of solid precipitates, and the obtained solid is filtered and dried to obtain the free compound. According to the general knowledge in the art and the experimental research of the inventors, it can be believed that the activity of the compounds of the present invention is not affected by whether the compound is in the salt form or the free form.

[0786] Biological test

[0787] Test Example 1: Plasma clot degradation experiment

[0788] 1. Experimental purpose

[0789] To determine the inhibitory effect of the compounds of the present invention on the degradation of human plasma clots.

[0790] 2. Experimental materials and instruments

[0791]

[0792] 3. Experimental steps

[0793] 3.1 Collect fresh and healthy human blood, use 0.109M trisodium citrate as an anticoagulant, mix 1 part of anticoagulant + 9 parts of blood, centrifuge at 2000x g for 20 minutes at room temperature, collect the supernatant (i.e., plasma), aliquot and store at -80°C for later use.

[0794] 3.2 On the day of the experiment, thaw the plasma in a 37°C water bath, and preheat all reagents except tPA to 37°C.

[0795] 3.3 Add 12.5 μL of 80 mM CaCl2 (HEPES buffer, pH 7.4) to a 96-well plate, and then add 25 μL of different concentrations of the test compound diluted with normal saline. Add an equal volume of normal saline to the negative control wells.

[0796] 3.4 Mix 50 μL of preheated plasma with 12.5 μL of 4 nM tPA (HEPES buffer, pH 7.4), immediately add it to the 96-well plate, detect the absorbance at 405 nm, read the value every 2 minutes, and continuously measure for 15 hours.

[0797] 3.5 The absorption value changes with time, first rising and then falling. The median time corresponding to the absorption value in the falling stage minus the median time corresponding to the absorption value in the rising stage is the plasma clot degradation time (Clot lysis time). Taking the plasma clot degradation time of the negative control well as a reference, calculate the plasma clot degradation time in the wells with different concentrations of the compound, and obtain the inhibition rate:

[0798] Inhibition rate % = (1 - negative control well Clot lysis time / compound well Clot lysis time ) × 100%

[0799] 3.6 Fitting the dose - effect curve

[0800] Taking the log value of the compound concentration as the X - axis and the percentage inhibition rate as the Y - axis, use the log(inhibitor) vs. response - variable slope fitting of the analysis software GraphPad Prism 5 to fit the dose - effect curve, so as to obtain the IC 50 value of each compound on cell activity.

[0801] Calculation formula: Y = min+(max - min) / (1 + 10^((LogIC 50 - X)×Hillslope)).

[0802] The plasma clot degradation activity of the compounds of the present invention is shown in Table 1.

[0803] Table 1 Determination results of the plasma clot degradation activity of compounds

[0804]

[0805]

[0806] Note: The IC 50 values of the compounds shown in Table 1 are not the absolute values measured in the experiment, but are calculated by taking the IC 50 value of tranexamic acid as a reference, and obtaining the ratio of the IC 50 value of each compound to the IC 50 value of tranexamic acid.

[0807] Tranexamic acid is the most widely used hemostatic drug in current clinical practice. As shown in Table 1, the in vitro plasma clot degradation inhibitory activity of the compounds provided by the present invention is higher than that of tranexamic acid, and has good clinical application prospects.

[0808] Test Example 2: Rat PK test

[0809] 1. Experimental purpose

[0810] By measuring the plasma drug concentration after intravenous administration to rats, the pharmacokinetic properties of the compounds of the present invention in rats were studied.

[0811] 2. Experimental animals

[0812] SD rats, SFP grade, male, N = 3, source: Shanghai SIPPR-BK Laboratory Animal Co., Ltd.

[0813] 3. Drug preparation and administration

[0814] Weigh the compound and dissolve it in normal saline. After preparing the administration solution, filter it through a membrane, and perform preparation analysis on the administration solution before and after filtration.

[0815] Preparation: An intravenous injection administration solution of 0.2 mg / mL.

[0816] One day before the experiment, the rats were fasted overnight and fed 4 hours after administration.

[0817] On the day of the experiment, administer the drug according to the protocol in Table 2. At each time point after administration, collect approximately 200 μL of blood from the jugular vein of the rats and place it in a heparin sodium anticoagulant tube. After collecting the blood samples, place them on ice and centrifuge to separate the plasma within 1 hour (centrifugation conditions: 6800 g, 6 minutes, 2 - 8 °C). Store the plasma samples in a -80 °C refrigerator before analysis.

[0818] Table 2 Drug administration protocol

[0819]

[0820] 4. Bioanalysis

[0821] An LC-MS / MS analytical method for determining the concentration of the compound in rat plasma was established to determine the concentration of the compound in the biological samples obtained in this experiment.

[0822] Based on the blood drug concentration data at different time points, use Phoenix WinNonlin 7.0 to calculate the pharmacokinetic parameters.

[0823] The experimental results show that the compounds provided by the present invention have high blood drug concentration and exposure in vivo, good safety, and good clinical application prospects.

Claims

1. The compound represented by Formula I, its pharmaceutically acceptable salts, wherein, R1 is H or a halogen; R2 is selected from H, substituted or unsubstituted C1-C6 alkyl, wherein the substituted C 1- C6 alkyl is substituted by one or more groups selected from methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, benzyl, fluorine, chlorine, bromine, iodine, amino, and hydroxyl; R3 is selected from hydrogen, hydroxyl, C1-C6 alkyl, C4-C 10 heteroalicyclic group; n = 0, 1 or 2.

2. The compound represented by claim 1, its pharmaceutically acceptable salts, characterized in that, R2 is selected from benzyl, 2-methylpropyl, neopentyl, phenethyl, isopropyl, propyl, 3,3-dimethylbutyl, isopentyl, 4-methoxyphenethyl, cyclohexylmethyl, cyclohexylethyl, phenylpropyl.

3. The compound represented by claim 1 or 2, its pharmaceutically acceptable salts, characterized in that, R3 is hydrogen, a hydroxyl group or a morpholinyl group.

4. The following compounds, their pharmaceutically acceptable salts: (1) 5,6,7,8 - Tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (2) 3 - Fluoro - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (3) 8 - Hydroxy - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (4) 7 - Benzyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (5) 8 - Morpholino - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (6) 7 - (2 - Methylpropyl) - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (7) 7 - Neopentyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (8) 7 - Phenethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (9) 7 - Isopropyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (10) 7 - Propyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (11) 7 - (3,3 - Dimethylbutyl) - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (12) 7 - Isoamyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (13) 7 - (4 - Methoxyphenethyl) - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (14) 7 - (Cyclohexylmethyl) - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (15) 7 - Cyclohexylethyl - 5,6,7,8 - tetrahydro - 1,6 - naphthyridine - 2 - sulfonic acid; (16) 7-(3-Phenylpropyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-sulfonic acid.

5. A pharmaceutical composition, characterized in that Comprising the compound according to any one of claims 1-4, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

6. Use of the compound according to any one of claims 1-4, its pharmaceutically acceptable salt or the pharmaceutical composition according to claim 5 for the preparation of a medicament.

7. The use according to claim 6, characterized in that The drug has coagulation and hemostatic activities.

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